Metabotrophic glutamate receptor 5 modulators and methods use thereof

ABSTRACT

Compounds that modulate GluR5 activity and methods of using the same are disclosed.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 61/494,731, filed Jun. 8, 2011. The entire contents of the foregoingapplication are hereby incorporated by reference.

BACKGROUND

The amino acid L-glutamate (which herein is referred to simply asglutamate) is the principal excitatory neurotransmitter in the brain andother elements of the central nervous system of mammals. Glutamate bindsto neurons and activates cell surface receptors. Glutamate hassignificant roles in motor control, cognitive function, sensoryperception, and acts as a mediator of persistent changes in the strengthof synaptic signaling (synaptic plasticity), thereby modulating longterm potentiation (LTP) and long term depression (LTD), which form thebasis of learning and memory. Many neurological and neuropsychiatricdisorders, including, but not limited to, psychosis spectrum disorders,schizophrenia and other cognitive deficits, are associated withaberrations in the function of (or the regulation by, or the regulationof) glutamate signaling systems.

Glutamate mediates its effect via two distinct types of receptors, theionotropic receptors and the metabotropic receptors. The family of themetabotropic receptors (mGlu or mGluR) consists of eight differentsubtypes, which are further classified into three subgroups based onsequence homology, effector coupling and pharmacology. In particular,group I mGlu receptors (mGluR1 and mGluR5) are positively coupled tophospholipase C, while group II mGlu receptors (mGluR2 and mGluR3) andgroup III receptors (mGluR4, mGluR6, mGluR7, and mGluR8) are negativelycoupled to adenylate cyclase (Conn et al. Annu. Rev. Pharmacol. Toxicol.1997; 37:205-37).

mGluR5, which is widely expressed in the central nervous system, has atleast two discrete allosteric binding sites, in addition to theorthosteric site, and has been implicated in a range of physiologicalfunctions, including phosphoinositide hydrolysis responses, modulationof potassium and voltage dependent calcium channels, modulation ofligand-gated ion channels and acting as a presynaptic autoreceptor atglutamatergic synapses, thereby modulating glutamate release (Conn etal., supra). Accordingly, development of therapeutic agents thatmodulate mGluR5 via direct agonism or antagonism or by positive ornegative allosteric modulation may prove useful for treatment ofdisorders influenced by the forgoing physiological functions, such asneurological disorders, neuropsychiatric disorders, GERD, drug addictionand alcohol addiction.

SUMMARY

The present invention is based, at least in part, on the discovery thatthe compounds as disclosed herein are allosteric modulators of mGluR5,for example, negative or positive allosteric modulators.

In various embodiments, a compound of formula (I) or a pharmaceuticallyacceptable salt thereof is provided:

wherein

Q is CR⁹ or N;

m and n are each independently 0 or 1;

X is F, Cl, Br, or I;

R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are each independently hydrogen, X,alkyl, heteroalkyl, cycloalkyl, or alkenyl; or any two of R¹, R², R³,R⁴, R⁵ and R⁶ together with the atoms to which they are attached, form acycloalkyl ring; and

R⁹ is hydrogen or alkyl;

provided that

at least one of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ is either X, or alkylor heteroalkyl substituted with at least one X; or a cycloalkyl ringformed by any two of R¹, R², R³, R⁴, R¹ and R⁶ together with the atomsto which they are attached is substituted with at least one X;

at least one of R³ and R⁴ is not hydrogen;

when m and n are both 1, Q is CH, and R¹, R², R⁴, R⁵, and R⁶ are all H,then R³ is not CF₃ or F;

when m and n are both 1, Q is CH, and R¹, R², R⁵, and R⁶ are all H, thenR³ and R⁴ are not both F;

when m and n are both 1, Q is CH, R¹, R², R⁵, and R⁶ are all H, and R³is unsubstituted alkyl, then R⁴ is not F; and

when m is 1, n is 0, Q is CH, R¹, R², R⁵, and R⁶ are all H, and R³ is Hor F, then R⁴ is not F.

In various embodiments, a compound of formula (II) or a pharmaceuticallyacceptable salt thereof is provided:

wherein

Q is CR⁷ or N;

G is CH₂ or O

R¹ and R² are independently hydrogen, alkyl, cyano, or heteroalkyl; orR¹ and R² together with the atom to which they are attached form acycloalkyl or heterocycloalkyl ring; and

R⁷ is selected from hydrogen and alkyl

provided that

when Q is N and G is CH₂, then at least one of R¹ and R² is nothydrogen;

when Q is N, G is CH₂, and one of R¹ and R² is methyl, then the other ofR¹ and R² is not hydrogen or methyl;

when Q is N, G is CH₂, and one of R¹ and R² is hydroxymethyl ormethoxymethyl, then the other of R¹ and R² is not hydrogen; and

when Q is N, G is CH₂, and R¹ and R² together with the atom to whichthey are attached form a heterocycloalkyl ring, then R¹ and R² togetherare not —(CH₂)₂O(CH₂)₂—.

In various embodiments, a compound of formula (III) or apharmaceutically acceptable salt thereof is provided:

wherein

R¹, R², R³, and R⁴ are each independently hydrogen, alkyl, hydroxyl,alkenyl, heteroalkyl, or cyano; or

R¹ and R² or R³ and R⁴ together with the atom to which they are attachedform a cycloalkyl or heterocycloalkyl ring; or

R² and R³ together with the atoms to which they are attached form acycloalkyl ring;

R⁵ is hydrogen or alkyl;

R⁶, R⁷, and R⁸ are each independently hydrogen, CN, heteroalkyl, alkyl,or X; and

X is F, Cl, Br, or I;

provided that

R³ and R⁴ cannot together form ═CH₂;

when R¹, R², R³, and R⁴ are all hydrogen, then at least one of R⁵, R⁶,R⁷, and R⁸ is not hydrogen;

when both R¹ and R² are methyl, then at least one of R³, R⁴, R⁵, R⁶, R⁷,and R⁸ is other than hydrogen;

when both R³ and R⁴ are methyl, then at least one of R¹, R², R⁵, R⁶, R⁷,and R⁸ is not hydrogen;

when one of R¹, R², R³, and R⁴ is methyl, and the other three of R¹, R²,R³, and R⁴ are all hydrogen, then at least one of R⁵, R⁶, R⁷, and R⁸ isnot hydrogen;

when one of R¹ and R² is hydroxymethyl or methoxymethyl and the other ofR¹ and R² is hydrogen, then at least one of R³, R⁴, R⁵, R⁶, R⁷, and R⁸is not hydrogen;

when one of R³ and R⁴ is hydroxymethyl, hydroxy, methoxy, methoxymethyl,or fluoro, and the other of R³ and R⁴ is hydrogen, then at least one ofR¹, R², R⁵, R⁶, R⁷, and R⁸ is not hydrogen;

when one of R³ and R⁴ is methyl and the other of R³ and R⁴ is hydroxylor methoxy, then at least one of R¹, R², R⁵, R⁶, R⁷, and R⁸ is nothydrogen;

when R³ and R⁴ are both F, then at least one of R¹, R², R⁶, R⁷, and R⁸is not hydrogen.

In various embodiments, a compound of formula (IV) or a pharmaceuticallyacceptable salt thereof is provided:

wherein

m and n are each independently 0 or 1;

R¹, R², R³, R⁴, R⁵ and R⁶ are each independently hydrogen, alkyl, orheteroalkyl; or

R¹ and R², R³ and R⁴, or R⁵ and R⁶ together with the atom to which theyare bonded form a cycloalkyl or heterocycloalkyl ring;

provided that

at least one of R¹, R², R³, R⁴, R⁵, and R⁶ is not hydrogen;

when m and n are both 1 or both m and n are 0, one of R³ and R⁴ ismethyl, and the other of R³ and R⁴ is hydrogen, then at least one of R¹,R², R⁵, and R⁶ is not hydrogen;

when m is 0, n is 1, and both R⁵ and R⁶ are methyl, then at least one ofR¹, R², R³, and R⁴ is not hydrogen;

when m is 1, n is 0, and both R³ and R⁴ are methyl, then at least one ofR¹, R², R⁵, and R⁶ is not hydrogen;

when m and n are both 0 and both R³ and R⁴ are methyl, then at least oneof R¹, R², R⁵ and R⁶ is not hydrogen; and when in and n are both 0, oneof R⁵ and R⁶ is hydroxymethyl or methoxymethyl, and the other of R⁵ andR⁶ is hydrogen, then at least one of R¹, R², R³, and R⁴ is not hydrogen.

In various embodiments, a compound of formula (V) or a pharmaceuticallyacceptable salt thereof is provided:

wherein

m and n are independently 0 or 1;

Z is

R¹, R², R³, R⁴, R⁵, and R⁶ are each independently hydrogen or alkyl;

Q is O or S;

R⁷ and R⁸ are hydrogen or alkyl; or R⁷ and R⁸ together with the atoms towhich they are attached form a cyclolalkyl, heterocycloalkyl, aryl, orheteroaryl ring;

provided that

when m is 1, n is 1, Z is

Q is S, R⁷ is methyl and R⁸ is hydrogen, one of R³ and R⁴ is methyl, andthe other of R³ and R⁴ is hydrogen, then at least one of R¹, R², R⁵ andR⁶ is not hydrogen.

In various embodiments, a compound of formula (VI) or a pharmaceuticallyacceptable salt thereof is provided:

wherein

m and n are independently 0 or 1;

L is —R⁸C═CR⁸—, —OC(R⁹)₂—, C(O)NR¹⁰—, or —NR¹⁰C(O)—;

X is F, Cl, Br, or I;

R¹, R², R³, R⁴, R⁵, and R⁶ are each independently hydrogen, alkyl, or X;

R⁷ is hydrogen or cyano;

each R⁸ is hydrogen or X;

R⁹ and R¹⁰ are each independently hydrogen or alkyl;

provided that

when m is 0, n is 0, L is —HC═CH—, one of R³ and R⁴ is methyl, the otherof R³ and R⁴ is hydrogen, R¹, R², R⁵, and R⁶ are all hydrogen, and R⁷ ishydrogen, then Pyr is not 2-pyridyl;

when m is 0, n is 1, L is —HC═CH—, R¹, R², R³, and R⁴ are all hydrogen,R⁵ and R⁶ are both methyl, and R⁷ is hydrogen or cyano, then Pyr is not

when m is 1, n is 0, L is —HC═CH—, R¹, R², R⁵, and R⁶ are all hydrogen,R³ and R⁴ are both methyl, and R⁷ is hydrogen or cyano, then Pyr is not

when m is 0, n is 1, L is —HC═CH—, R¹, R², R⁵, and R⁶ are all hydrogen,R³ and R⁴ are both methyl, and R⁷ is hydrogen or cyano, then Pyr is not

when m is 1, n is 0, L is —HC═CH—, R¹, R⁴, R⁵, and R¹ are all hydrogen,R¹ and R² are both methyl, and R⁷ is hydrogen or cyano, then Pyr is not

when m is 1, n is 1, L is —HC═CH—, one of R³ and R⁴ is methyl, the otherof R³ and R⁴ is hydrogen, R¹, R², R⁵, and R⁶ are all hydrogen, and R⁷ ishydrogen or cyano, then Pyr is not

and

when m is 1, n is 1, L is —HC═CH—, R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ areall hydrogen, then Pyr is not 2-pyridyl.

In various embodiments, a compound of formula (VII) or apharmaceutically acceptable salt thereof is provided:

wherein Z is

In various embodiments, a compound of formula (VIII) or apharmaceutically acceptable salt thereof is provided:

wherein

m and n are independently 0 or 1;

R¹, R², R³, R⁴, R⁵, and R⁶ are each independently hydrogen, alkyl, orheteroalkyl; or

R¹ and R², R³ and R, or R⁵ and R⁶ together with the atom to which theyare bonded form a cycloalkyl or heterocycloalkyl ring;

R⁷ is

R⁸ is H, F, Cl, Br, or I;

L is O, NH, —CH₂CH(CH₃)—, —CH₂O—, —CH═C(CH₃)—, —C(O)CH₂—, —C(O)CH(CH₃)—,—(CH₂)₃—, —CH₂OCH₂—, —NHC(O)NH—, —C(O)NHNHC(O)—,

X, Y, and Z are independently O, N, or S;

each Q is independently CH or N;

provided that

at least two occurrences of Q are CH; and

when m is 1, n is 1, and R¹, R², R³, R⁴, R⁵, R⁶; and R⁸ are allhydrogen, then R⁷ is not

In various embodiments, a compound of the following formulae or apharmaceutically acceptable salt thereof is provided:

In certain embodiments, the invention provides pharmaceuticalcompositions comprising a therapeutically effective amount of a compoundas disclosed herein and a pharmaceutically acceptable carrier.

In certain embodiments, the invention provides methods for treating adisorder or disease mediated by mGluR5, comprising administering to asubject in need thereof a therapeutically effective amount of a compoundas disclosed herein.

In certain embodiments, the invention provides methods for treatingneurological disorders, such as neurodegenerative diseases,neuropsychiatric diseases, affective disorders, loss of cognitivefunction, and learning and memory disorders, comprising administering toa subject in need thereof a therapeutically effective amount of acompound as disclosed herein.

In certain embodiments, methods are provided for treating psychosis,comprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound as disclosed herein.

In certain embodiments, methods are provided for treating schizophrenia,comprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound as disclosed herein.

In certain embodiments, methods are provided for treating Alzheimer'sdisease, comprising administering to a subject in need thereof atherapeutically effective amount of a compound as disclosed herein.

In certain embodiments, methods are provided for treating cognitivedisorders, comprising administering to a subject in need thereof atherapeutically effective amount of a compound as disclosed herein.

In certain embodiments, methods are provided for treating cognitiveimpairment associated with schizophrenia, comprising administering to asubject in need thereof a therapeutically effective amount of a compoundas disclosed herein.

In certain embodiments, methods are provided for treating tubularsclerosis.

In certain embodiments, the invention provides methods for modulatingmGluR5 in a subject by administering to the subject a therapeuticallyeffective amount of a compound as disclosed herein.

In certain embodiments, the invention provides methods for modulatingmGluR5 in a cell by contacting the cell with an effective amount of acompound as disclosed herein.

DETAILED DESCRIPTION OF THE INVENTION

Various embodiments of the invention are described herein. It will berecognized that features specified in each embodiment may be combinedwith other specified features to provide further embodiments.

As used herein, the articles “a” and “an” mean “one or more” or “atleast one,” unless otherwise indicated. That is, reference to anyelement of the present invention by the indefinite article “a” or “an”does not exclude the possibility that more than one of the element ispresent.

The use of any and all examples, or exemplary language (e.g., “such as”)provided herein is intended merely to better illuminate the inventionand is not intended to limit the scope of the invention.

Compounds

In certain embodiments, a compound of formula (I) or a pharmaceuticallyacceptable salt thereof is provided:

wherein

Q is CR⁹ or N;

m and n are each independently 0 or 1;

X is F, Cl, Br, or I;

R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are each independently hydrogen, X,alkyl, heteroalkyl, cycloalkyl, or alkenyl; or any two of R¹, R², R³,R⁴, R⁵ and R⁶ together with the atoms to which they are attached, form acycloalkyl ring; and

R⁹ is hydrogen or alkyl;

provided that

at least one of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ is either X, or alkylor heteroalkyl substituted with at least one X; or a cycloalkyl ringformed by any two of R¹, R², R³, R⁴, R¹ and R⁶ together with the atomsto which they are attached is substituted with at least one X;

at least one of R³ and R⁴ is not hydrogen;

when m and n are both 1, Q is CH, and R¹, R², R⁴, R⁵, and R⁶ are all H,then R³ is not CF₃ or F;

when m and n are both 1, Q is CH, and R¹, R², R⁵, and R⁶ are all H, thenR³ and R⁴ are not both F;

when m and n are both 1, Q is CH, R¹, R², R⁵, and R⁶ are all H, and R³is unsubstituted alkyl, then R⁴ is not F; and

when m is 1, n is 0, Q is CH, R¹, R², R⁵, and R⁶ are all H, and R³ is Hor F, then R⁴ is not F.

In certain embodiments, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are eachindependently hydrogen, X, alkyl, heteroalkyl, or alkenyl; or any two ofR¹, R², R³, R⁴, R⁵ and R⁶ together with the atoms to which they areattached, form a cycloalkyl ring

In certain embodiments, Q is CR⁹. In certain embodiments, Q is N. Incertain embodiments, Q is CH or N. In certain embodiments, Q is CH.

In certain embodiments, m is 0. In certain embodiments, m is 1. Incertain embodiments, n is 0. In certain embodiments, n is 1.

In certain embodiments, X is F. In certain embodiments, X is Cl. Incertain embodiments, X is Br. In certain embodiments, X is I.

In certain embodiments, R¹ is hydrogen. In certain embodiments, R¹ is X.In certain embodiments, R¹ is alkyl. In certain embodiments, R¹ isheteroalkyl. In certain embodiments, R¹ is alkenyl.

In certain embodiments, R² is hydrogen. In certain embodiments, R² is X.In certain embodiments, R² is alkyl. In certain embodiments, R² isheteroalkyl. In certain embodiments, R² is alkenyl.

In certain embodiments, R³ is hydrogen. In certain embodiments, R³ is X.In certain embodiments, R³ is alkyl. In certain embodiments, R³ isheteroalkyl. In certain embodiments, R³ is alkenyl.

In certain embodiments, R⁴ is hydrogen. In certain embodiments, R⁴ is X.In certain embodiments, R⁴ is alkyl. In certain embodiments, R⁴ isheteroalkyl. In certain embodiments, R⁴ is alkenyl.

In certain embodiments, R⁵ is hydrogen. In certain embodiments, R⁵ is X.In certain embodiments, R⁵ is alkyl. In certain embodiments, R⁵ isheteroalkyl. In certain embodiments, R⁵ is alkenyl.

In certain embodiments, R⁶ is hydrogen. In certain embodiments, R⁶ is X.In certain embodiments, R⁶ is alkyl. In certain embodiments, R⁶ isheteroalkyl. In certain embodiments, R⁶ is alkenyl.

In certain embodiments, R⁷ is hydrogen. In certain embodiments, R⁷ is X.In certain embodiments, R⁷ is alkyl. In certain embodiments, R⁷ isheteroalkyl. In certain embodiments, R⁷ is alkenyl.

In certain embodiments, R⁸ is hydrogen. In certain embodiments, R⁸ is X.In certain embodiments, R⁸ is alkyl. In certain embodiments, R⁸ isheteroalkyl. In certain embodiments, R⁸ is alkenyl.

In certain embodiments, R¹ and R² together with the atoms to which theyare attached, form a cycloalkyl ring. In certain embodiments, R¹ and R³together with the atoms to which they are attached, form a cycloalkylring. In certain embodiments, R¹ and R⁴ together with the atoms to whichthey are attached, form a cycloalkyl ring. In certain embodiments, R¹and R⁵ together with the atoms to which they are attached, form acycloalkyl ring. In certain embodiments, R¹ and R⁶ together with theatoms to which they are attached, form a cycloalkyl ring. In someembodiments, R¹ and R⁷ together with the atoms to which they areattached, form a cycloalkyl ring. In some embodiments, R¹ and R⁸together with the atoms to which they are attached, form a cycloalkylring.

In certain embodiments, R² and R³ together with the atoms to which theyare attached, form a cycloalkyl ring. In certain embodiments, R² and R⁴together with the atoms to which they are attached, form a cycloalkylring. In certain embodiments, R² and R⁵ together with the atoms to whichthey are attached, form a cycloalkyl ring. In certain embodiments, R²and R⁶ together with the atoms to which they are attached, form acycloalkyl ring. In certain embodiments, R² and R⁷ together with theatoms to which they are attached, form a cycloalkyl ring. In certainembodiments, R² and R⁸ together with the atoms to which they areattached, form a cycloalkyl ring.

In certain embodiments, R³ and R⁴ together with the atoms to which theyare attached, form a cycloalkyl ring. In certain embodiments, R³ and R⁵together with the atoms to which they are attached, form a cycloalkylring. In certain embodiments, R³ and R⁶ together with the atoms to whichthey are attached, form a cycloalkyl ring. In certain embodiments, R¹and R⁷ together with the atoms to which they are attached, form acycloalkyl ring. In certain embodiments, R³ and R⁸ together with theatoms to which they are attached, form a cycloalkyl ring.

In certain embodiments, R⁴ and R⁵ together with the atoms to which theyare attached, form a cycloalkyl ring. In certain embodiments, R⁴ and R⁶together with the atoms to which they are attached, form a cycloalkylring. In certain embodiments, R⁴ and R⁷ together with the atoms to whichthey are attached, form a cycloalkyl ring. In certain embodiments, R⁴and R⁸ together with the atoms to which they are attached, form acycloalkyl ring.

In certain embodiments, R⁵ and R⁶ together with the atoms to which theyare attached, form a cycloalkyl ring. In certain embodiments, R⁵ and R⁷together with the atoms to which they are attached, form a cycloalkylring. In certain embodiments, R⁵ and R⁸ together with the atoms to whichthey are attached, form a cycloalkyl ring.

In certain embodiments, R⁶ and R⁷ together with the atoms to which theyare attached, form a cycloalkyl ring. In certain embodiments, R⁶ and R⁸together with the atoms to which they are attached, form a cycloalkylring.

In certain embodiments, R⁷ and R⁸ together with the atoms to which theyare attached, form a cycloalkyl ring.

In certain embodiments, a compound of Formula (I) is

pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

As used herein “*” is used to denote a compound having at least onestereocenter, wherein the stereoisomers have been separated, but theabsolute stereochemistry has not been determined.

In certain embodiments, a compound of formula (II) or a pharmaceuticallyacceptable salt thereof is provided:

wherein

Q is CR⁷ or N;

G is CH₂ or O

R¹ and R² are independently hydrogen, alkyl, cyano, or heteroalkyl; orR¹ and R² together with the atom to which they are attached form acycloalkyl or heterocycloalkyl ring; and

R⁷ is selected from hydrogen and alkyl

provided that

when Q is N and G is CH₂, then at least one of R¹ and R² is nothydrogen;

when Q is N, G is CH₂, and one of R¹ and R² is methyl, then the other ofR¹ and R² is not hydrogen or methyl;

when Q is N, G is CH₂, and one of R¹ and R² is hydroxymethyl ormethoxymethyl, then the other of R¹ and R² is not hydrogen; and

when Q is N, G is CH₂, and R¹ and R² together with the atom to whichthey are attached form a heterocycloalkyl ring, then R¹ and R² togetherare not —(CH₂)₂O(CH₂)₂—.

In certain embodiments, Q is CR⁷. In certain embodiments, Q is N.

In certain embodiments, G is CH₂. In certain embodiments, G is O.

In certain embodiments, R¹ is hydrogen. In certain embodiments, R¹ isalkyl. In certain embodiments, R¹ is cyano. In certain embodiments, R¹is heteroalkyl.

In certain embodiments, R² is hydrogen. In certain embodiments, R² isalkyl. In certain embodiments, R² is cyano. In certain embodiments, R²is heteroalkyl.

In certain embodiments, R¹ and R² together with the atom to which theyare attached form a cycloalkyl ring. In certain embodiments, R¹ and R²together with the atom to which they are attached form aheterocycloalkyl ring.

In certain embodiments, R⁷ is hydrogen. In certain embodiments, R⁷ isalkyl.

In certain embodiments, a compound of Formula (II) is

a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of formula (III) or apharmaceutically acceptable salt thereof is provided:

wherein

R¹, R², R³, and R⁴ are each independently hydrogen, alkyl, hydroxyl,alkenyl, heteroalkyl, or cyano; or

R¹ and R² or R³ and R⁴ together with the atom to which they are attachedform a cycloalkyl or heterocycloalkyl ring; or

R² and R³ together with the atoms to which they are attached form acycloalkyl ring;

R⁵ is hydrogen or alkyl;

R⁶, R⁷, and R⁸ are each independently hydrogen, CN, heteroalkyl, alkyl,or X; and

X is F, Cl, Br, or I;

provided that

R³ and R⁴ cannot together form ═CH₂;

when R¹, R², R³, and R⁴ are all hydrogen, then at least one of R⁵, R⁶,R⁷, and R⁸ is not hydrogen;

when both R¹ and R² are methyl, then at least one of R³, R⁴, R⁵, R⁶, R⁷,and R⁸ is other than hydrogen;

when both R³ and R⁴ are methyl, then at least one of R¹, R², R⁵, R⁶, R⁷,and R⁸ is not hydrogen;

when one of R¹, R², R³, and R⁴ is methyl, and the other three of R¹, R²,R³, and R¹ are all hydrogen, then at least one of R⁵, R⁶, R⁷, and R⁸ isnot hydrogen;

when one of R¹ and R² is hydroxymethyl or methoxymethyl and the other ofR¹ and R² is hydrogen, then at least one of R³, R⁴, R⁵, R⁶, R⁷, and R⁸is not hydrogen;

when one of R³ and R⁴ is hydroxymethyl, hydroxy, methoxy, methoxymethyl,or fluoro, and the other of R³ and R⁴ is hydrogen, then at least one ofR¹, R², R⁵, R⁶, R⁷, and R⁸ is not hydrogen;

when one of R³ and R⁴ is methyl and the other of R³ and R⁴ is hydroxylor methoxy, then at least one of R¹, R², R⁵, R⁶, R⁷, and R⁸ is nothydrogen;

when R³ and R⁴ are both F, then at least one of R¹, R², R⁵, R⁶, R⁷, andR⁸ is not hydrogen.

In certain embodiments, R⁶, R⁷, and R⁸ are all hydrogen.

In certain embodiments, R¹ is hydrogen. In certain embodiments, R¹ isalkyl. In certain embodiments, R¹ is hydroxyl. In certain embodiments,R¹ is alkenyl. In certain embodiments, R¹ is heteroalkyl. In certainembodiments, R¹ is cyano.

In certain embodiments, R² is hydrogen. In certain embodiments, R² isalkyl. In certain embodiments, R² is hydroxyl. In certain embodiments,R² is alkenyl. In certain embodiments, R² is heteroalkyl. In certainembodiments, R² is cyano.

In certain embodiments, R³ is hydrogen. In certain embodiments, R³ isalkyl. In certain embodiments, R³ is hydroxyl. In certain embodiments,R³ is alkenyl. In certain embodiments, R³ is heteroalkyl. In certainembodiments, R³ is cyano.

In certain embodiments, R⁴ is hydrogen. In certain embodiments, R⁴ isalkyl. In certain embodiments, R⁴ is hydroxyl. In certain embodiments,R⁴ is alkenyl. In certain embodiments, R⁴ is heteroalkyl. In certainembodiments, R⁴ is cyano.

In certain embodiments, R¹ and R² together with the atom to which theyare attached form a cycloalkyl ring. In certain embodiments, R¹ and R²together with the atom to which they are attached form aheterocycloalkyl ring.

In certain embodiments, R³ and R⁴ together with the atom to which theyare attached form a cycloalkyl ring. In certain embodiments, R³ and R⁴together with the atom to which they are attached form aheterocycloalkyl ring.

In certain embodiments, R² and R³ together with the atoms to which theyare attached form a cycloalkyl ring.

In certain embodiments, R⁵ is hydrogen. In certain embodiments, R⁵ isalkyl.

In certain embodiments, R⁶ is hydrogen. In certain embodiments, R⁶ isCN. In certain embodiments, R⁶ is heteroalkyl. In certain embodiments,R⁶ is alkyl. In certain embodiments, R⁶ is X.

In certain embodiments, R⁷ is hydrogen. In certain embodiments, R⁷ isCN. In certain embodiments, R⁷ is heteroalkyl. In certain embodiments,R⁷ is alkyl. In certain embodiments, R⁷ is X.

In certain embodiments, R⁸ is hydrogen. In certain embodiments, R⁸ isCN. In certain embodiments, R⁸ is heteroalkyl. In certain embodiments,R⁸ is alkyl. In certain embodiments, R⁸ is X.

In certain embodiments, X is F. In certain embodiments, X is Cl. Incertain embodiments, X is Br. In certain embodiments, X is I.

In certain embodiments, a compound of formula (III) is

or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of formula (III) is

or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of formula (IV) or a pharmaceuticallyacceptable salt thereof is provided:

wherein

m and n are each independently 0 or 1;

R¹, R², R³, R⁴, R⁵, and R⁶ are each independently hydrogen, alkyl, orheteroalkyl; or

R¹ and R², R³ and R⁴, or R⁵ and R⁶ together with the atom to which theyare bonded form a cycloalkyl or heterocycloalkyl ring;

provided that

at least one of R¹, R², R³, R⁴, R⁵, and R⁶ is not hydrogen;

when m and n are both 1 or both m and n are 0, one of R³ and R⁴ ismethyl, and the other of R³ and R⁴ is hydrogen, then at least one of R¹,R², R⁵, and R⁶ is not hydrogen;

when m is 0, n is 1, and both R⁵ and R⁶ are methyl, then at least one ofR¹, R², R³, and R⁴ is not hydrogen;

when m is 1, n is 0, and both R³ and R⁴ are methyl, then at least one ofR¹, R², R⁵, and R⁶ is not hydrogen;

when m and n are both 0 and both R³ and R⁴ are methyl, then at least oneof R¹, R², R⁵ and R⁶ is not hydrogen; and

when m and n are both 0, one of R⁵ and R⁶ is hydroxymethyl ormethoxymethyl, and the other of R⁵ and R⁶ is hydrogen, then at least oneof R¹, R², R³, and R⁴ is not hydrogen.

In certain embodiments, R¹, R², R³, R⁴, R⁵, and R⁶ do not comprise anyhalogen atoms.

In certain embodiments, m is 0. In certain embodiments, m is 1. Incertain embodiments, n is 0. In certain embodiments, n is 1.

In certain embodiments, R¹ is hydrogen. In certain embodiments, R¹ isalkyl. In certain embodiments, R¹ is heteroalkyl.

In certain embodiments, R² is hydrogen. In certain embodiments, R² isalkyl. In certain embodiments, R² is heteroalkyl.

In certain embodiments, R³ is hydrogen. In certain embodiments, R³ isalkyl. In certain embodiments, R³ is heteroalkyl.

In certain embodiments, R⁴ is hydrogen. In certain embodiments, R⁴ isalkyl. In certain embodiments, R⁴ is heteroalkyl.

In certain embodiments, R⁵ is hydrogen. In certain embodiments, R⁵ isalkyl. In certain embodiments, R⁵ is heteroalkyl.

In certain embodiments, R⁶ is hydrogen. In certain embodiments, R⁶ isalkyl. In certain embodiments, R⁶ is heteroalkyl.

In certain embodiments, R¹ and R² together with the atom to which theyare bonded form a cycloalkyl ring. In certain embodiments, R¹ and R²together with the atom to which they are bonded form a heterocycloalkylring.

In certain embodiments, R³ and R⁴ together with the atom to which theyare bonded form a cycloalkyl ring. In certain embodiments, R³ and R⁴together with the atom to which they are bonded form a heterocycloalkylring.

In certain embodiments, R⁵ and R⁶ together with the atom to which theyare bonded form a cycloalkyl ring. In certain embodiments, R⁵ and R⁶together with the atom to which they are bonded form a heterocycloalkylring.

In certain embodiments, a compound of Formula (IV) is

or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of formula (V) or a pharmaceuticallyacceptable salt thereof is provided:

wherein

m and n are independently 0 or 1;

Z is

R¹, R², R³, R⁴, R⁵, and R⁶ are each independently hydrogen or alkyl;

Q is O or S;

R⁷ and R⁸ are hydrogen or alkyl; or R⁷ and R⁸ together with the atoms towhich they are attached form a cyclolalkyl, heterocycloalkyl, aryl, orheteroaryl ring;

provided that

when m is 1, n is 1, Z is

Q is S, R⁷ is methyl and R⁸ is hydrogen, one of R³ and R⁴ is methyl, andthe other of R³ and R⁴ is hydrogen, then at least one of R¹, R², R⁵ andR⁶ is not hydrogen.

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, R¹ is hydrogen. In certain embodiments, R¹ isalkyl.

In certain embodiments, R² is hydrogen. In certain embodiments, R² isalkyl.

In certain embodiments, R³ is hydrogen. In certain embodiments, R³ isalkyl.

In certain embodiments, R⁴ is hydrogen. In certain embodiments, R⁴ isalkyl.

In certain embodiments, R⁵ is hydrogen. In certain embodiments, R⁵ isalkyl

In certain embodiments, R⁶ is hydrogen. In certain embodiments, R⁶ isalkyl.

In certain embodiments, R⁷ is hydrogen. In certain embodiments, R⁷ isalkyl.

In certain embodiments, R⁸ is hydrogen. In certain embodiments, R⁸ isalkyl.

In certain embodiments, R⁷ and R⁸ together with the atoms to which theyare attached form a cyclolalkyl ring. In certain embodiments, R⁷ and R⁸together with the atoms to which they are attached form aheterocycloalkyl ring. In certain embodiments, R⁷ and R⁸ together withthe atoms to which they are attached form an aryl ring. In certainembodiments, R⁷ and R⁸ together with the atoms to which they areattached form a heteroaryl ring.

In certain embodiments, a compound of Formula (V) is

or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of formula (VI) or a pharmaceuticallyacceptable salt thereof is provided:

wherein

m and n are independently 0 or 1;

L is —R⁸C═CR⁸—, —OC(R⁹)₂, C(O)NR¹⁰—, or —NR¹⁰C(O)—;

X is F, Cl, Br, or I;

R¹, R², R³, R⁴, R⁵, and R⁶ are each independently hydrogen, alkyl, or X;

R⁷ is hydrogen or cyano;

each R⁸ is hydrogen or X;

R⁹ and R¹⁰ are each independently hydrogen or alkyl;

provided that

when m is 0, n is 0, L is —HC═CH—, one of R³ and R⁴ is methyl, the otherof R¹ and R⁴ is hydrogen, R¹, R², R⁵, and R⁶ are all hydrogen, and R⁷ ishydrogen, then Pyr is not 2-pyridyl;

when m is 0, n is 1, L is —HC═CH—, R¹, R², R³, and R⁴ are all hydrogen,R⁵ and R⁶ are both methyl, and R⁷ is hydrogen or cyano, then Pyr is not2-pyridyl, preferably Pyr is not

when m is 1, n is 0, IL is —HC═CH—, R¹, R², R, and R⁶ are all hydrogen,R¹ and R⁴ are both methyl, and R⁷ is hydrogen or cyano, then Pyr is not2-pyridyl, preferably Pyr is not

when m is 0, n is 1, L is —HC═CH—, R¹, R², R⁵, and R⁶ are all hydrogen,R³ and R⁴ are both methyl, and R⁷ is hydrogen or cyano, then Pyr is notthen Pyr is not 2-pyridyl, preferably Pyr is not

when m is 1, n is 0, L is —HC═CH—, R³, R⁴, R⁵, and R⁶ are all hydrogen,R¹ and R² are both methyl, and R⁷ is hydrogen or cyano, then Pyr is notthen Pyr is not 2-pyridyl, preferably Pyr is not

when in is 1, n is 1, L is —HC═CH—, one of R³ and R⁴ is methyl, theother of R³ and R⁴ is hydrogen. R¹, R², R⁵, and R⁶ are all hydrogen, andR⁷ is hydrogen or cyano, then Pyr is not then Pyr is not 2-pyridyl,preferably Pyr is not

and

when m is 1, n is 1, L is —HC═CH—, R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ areall hydrogen, then Pyr is not 2-pyridyl.

In certain embodiments, m is 0. In certain embodiments, n is 1. Incertain embodiments, n is 0. In certain embodiments, n is 1.

In certain embodiments, L is —R⁸C═CR⁸. In certain embodiments, L is—OC(R⁹)₂—. In certain embodiments, L, is C(O)NR¹⁰—. In certainembodiments, L is —NR¹⁰C(O)—.

In certain embodiments, X is F. In certain embodiments, X is Cl. Incertain embodiments, X is Br. In certain embodiments, X is I.

In certain embodiments, R¹ is hydrogen. In certain embodiments, R¹ isalkyl. In certain embodiments, R¹ is X.

In certain embodiments, R² is hydrogen. In certain embodiments, R² isalkyl. In certain embodiments, R² is X.

In certain embodiments, R³ is hydrogen. In certain embodiments, R³ isalkyl. In certain embodiments, R³ is X.

In certain embodiments, R⁴ is hydrogen. In certain embodiments, R⁴ isalkyl. In certain embodiments, R⁴ is X.

In certain embodiments, R⁵ is hydrogen. In certain embodiments, R⁵ isalkyl. In certain embodiments, R⁵ is X.

In certain embodiments, R⁶ is hydrogen. In certain embodiments, R⁶ isalkyl. In certain embodiments, R⁶ is X.

In certain embodiments, R⁷ is hydrogen. In certain embodiments, R⁷ iscyano.

In certain embodiments, R⁸ is hydrogen. In certain embodiments, R⁸ is X.

In certain embodiments, R⁹ is hydrogen. In certain embodiments, R⁹ isalkyl.

In certain embodiments, R¹⁰ is alkyl. In certain embodiments, R¹⁰ ishydrogen.

In certain embodiments, a compound of Formula (VI) is

or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of formula (VII) or apharmaceutically acceptable salt thereof is provided:

wherein Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, Z is

In certain embodiments, a compound of Formula (VII) is

or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of formula (VIII) or apharmaceutically acceptable salt thereof is provided:

wherein

m and n are independently 0 or 1;

R¹, R², R³, R⁴, R⁵, and R⁶ are each independently hydrogen, alkyl, orheteroalkyl; or

R¹ and R², R³ and R⁴, or R⁵ and R⁶ together with the atom to which theyare bonded form a cycloalkyl or heterocycloalkyl ring;

R⁷ is

R⁸ is H, F, Cl, Br, or I;

L is O, NH, —CH₂CH(CH₃)—, —CH₂O—, —CH═C(CH₃)—, —C(O)CH₂—, —C(O)CH(CH₃)—,—(CH₂)₃—, —CH₂OCH₂—, —NHC(O)NH—, —C(O)NHNHC(O)—,

X, Y, and Z are independently O, N, or S;

each Q is independently CH or N;

provided that

at least two occurrences of Q are CH; and

when m is 1, n is 1, and R¹, R², R³, R⁴, R⁵, R⁶, and R⁸ are allhydrogen, then R⁷ is not

In certain embodiments, m is 0. In certain embodiments, m is 1.

In certain embodiments, n is 0. In certain embodiments, n is 1.

In certain embodiments, R¹ is hydrogen. In certain embodiments, R² ishydrogen.

In certain embodiments, R³ is hydrogen. In certain embodiments, R³ isalkyl (e.g., methyl).

In certain embodiments, R⁴ is hydrogen. In certain embodiments, R⁴ isalkyl (e.g., methyl)

In certain embodiments, R⁵ is hydrogen. In certain embodiments, R⁵ isalkyl (e.g., methyl).

In certain embodiments, R⁶ is hydrogen. In certain embodiments, R⁶ isalkyl (e.g., methyl).

In certain embodiments, L is O, NH, —CH₂CH(CH₃)—, —CH₂O—, —CH═C(CH₃)—,—C(O)CH₂—, —C(O)CH(CH₃)—, —(CH₂)₃—, —CH₂OCH₂—, —NHC(O)NH—,—C(O)NHNHC(O)—,

In certain embodiments, L is O. In certain embodiments, L is —CH₂O—. Incertain embodiments, L is NH. In certain embodiments, L is —CH₂CH(CH₃)—.In certain embodiments, L is —CH—C(CH₃)—. In certain embodiments, L is—C(O)CH₂—. In certain embodiments, L is —C(O)CH(CH₃)—. In certainembodiments, L is

In certain embodiments, L is

In certain embodiments, L is —(CH₂)₃—. In certain embodiments, L is—CH₂OCH₂—. In certain embodiments, L is —NHC(O)NH—. In certainembodiment L is

In certain embodiments, L is

In certain embodiments, L is —C(O)NHNHC(O)—. In certain embodiments, Lis

In certain embodiments, L is

In certain embodiments, L is

In certain embodiments, X is N. In certain embodiments, Y is O. Incertain embodiments, Z is N. In certain embodiments, X is N, Y is O andZ is N.

In certain embodiments, L is

In certain embodiments, X is N. In certain embodiments. Y is O. Incertain embodiments, Y is S. In certain embodiments, Z is N. In certainembodiments, X is N, Y is O and Z is N. In certain embodiments, X is N,Y is S and Z is N.

In certain embodiments, L is

In certain embodiments, X is N. In certain embodiments, Y is N. Incertain embodiments, X is N and Y is N.

In certain embodiments, L is

In certain embodiments, X is N. In certain embodiments, Y is N. Incertain embodiments, X is N and Y is N.

In certain embodiments, L is

In certain embodiments, X is N. In certain embodiments, Y is O. Incertain embodiments, X is N and Y is O.

In certain embodiments L is

In certain embodiments, X is O. In certain embodiments, X is S. Incertain embodiments, Y is N. In certain embodiments, X is O and Y is N.In certain embodiments, X is S and Y is N.

In certain embodiments, L is

In certain embodiments, X is O. In certain embodiments, X is S. Incertain embodiments, Y is N. In certain embodiments, X is O and Y is N.In certain embodiments, X is S and Y is N.

In certain embodiments, L is

In certain embodiments, X is N. In certain embodiments, Y is S. Incertain embodiments, X is N and Y is S.

In certain embodiments, L is

In certain embodiments, X is N. In certain embodiments Y is N. Incertain embodiments, Z is N. In certain embodiments, X, Y and Z are N.

In certain embodiments, L is

In certain embodiments, X is N. In certain embodiments Y is N. Incertain embodiments, Z is N. In certain embodiments, X, Y and Z are N.

In certain embodiments, L is

In certain embodiments, each occurrence of Q is CH. In certainembodiments, one occurrence of Q is N and each remaining occurrence of Qis CH. In certain embodiments, two occurrences of Q are N and twooccurrences of Q are CH. In certain embodiments, L is

In certain embodiments, L is

In certain embodiments, L is

In certain embodiments, L is

In certain embodiments, L is

In certain embodiments, R⁷ is

In certain embodiments, R⁷ is

In certain embodiments, R⁸ is H. In certain embodiments, R⁸ is F.

In certain embodiments, a compound of Formula (VIII) is

In certain embodiments, a compound of the invention is

or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of the invention is

or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of the invention is

As used herein, the term “alkyl” includes linear saturated monovalenthydrocarbon radicals that have 1 to 20 (C₁₋₂₀), 1 to 15 (C₁₋₁₅), 1 to 12(C₁₋₁₂), 1 to 10 (C₁₋₁₀), or 1 to 6 (C₁₋₆) carbon atoms, or branchedsaturated monovalent hydrocarbon radicals having 3 to 20 (C₃₋₂₀), 3 to15 (C₃₋₁₅), 3 to 12 (C₃₋₁₂), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbonatoms. As used herein, linear C₁₋₆ and branched C₃₋₆ alkyl groups arealso referred to as “lower alkyl.” Examples of alkyl groups include, butare not limited to, methyl, ethyl, propyl (including all isomeric forms,e.g., n-propyl, isopropyl), butyl (including all isomeric forms, e.g.,n-butyl, isobutyl, t-butyl), pentyl (including all isomeric forms), andhexyl (including all isomeric forms). For example, C₁₋₆ alkyl refers toa linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atomsor a branched saturated monovalent hydrocarbon radical of 3 to 6 carbonatoms. In certain embodiments, the alkyl is optionally substituted asdescribed herein elsewhere. In some embodiments, the alkyl is optionallysubstituted with one or more halo (“haloalkyl”).

As used herein, and unless otherwise specified, the term “alkenyl”refers to a linear or branched monovalent hydrocarbon radical, whichcontains one or more, in one embodiment, one to five, carbon-carbondouble bonds. The alkenyl may be optionally substituted with one or moresubstituents. The term “alkenyl” encompasses radicals having “cis” and“trans” configurations, or alternatively, “E” and “Z” configurations, asappreciated by those of ordinary skill in the art. As used herein, theterm “alkenyl” encompasses both linear and branched alkenyl, unlessotherwise specified. For example, C₂₋₆ alkenyl refers to a linearunsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or abranched unsaturated monovalent hydrocarbon radical of 3 to 6 carbonatoms. In certain embodiments, the alkenyl is a linear monovalenthydrocarbon radical of 2 to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 12(C₂₋₁₂), 2 to 10 (C₂₋₁₀), or 2 to 6 (C₂₋₆) carbon atoms, or a branchedmonovalent hydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to12 (C₃₋₁₂), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examples ofalkenyl groups include, but are not limited to, ethenyl, propen-1-yl,propen-2-yl, allyl, butenyl, and 4-methylbutenyl. In certainembodiments, the alkenyl is optionally substituted as described hereinelsewhere.

As used herein, and unless otherwise specified, the term “alkoxy” refersto a straight or branched chain, containing the stated number of carbonatoms and an oxygen atom at the terminal position through which thealkoxy group is attached to the molecule. Examples of alkoxy include,but are not limited to, —O—CH₃, —O—CF₃, —O—CH₂—CH₃, —O—CH₂—CH₂—CH₃,—O—CH—(CH₃)₂, and —O—CH₂—CH₂—O—CH₃. In one embodiment, the alkoxy isoptionally substituted as described herein elsewhere.

As used herein, and unless otherwise specified, the term “alkynyl”refers to a linear or branched monovalent hydrocarbon radical, whichcontains one or more, in one embodiment, one to five, carbon-carbontriple bonds. The alkynyl may be optionally substituted with one or moresubstituents. The term “alkynyl” also encompasses both linear andbranched alkynyl, unless otherwise specified. In certain embodiments,the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20(C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 12 (C₂₋₁₂), 2 to 10 (C₂₋₁₀), or 2 to 6(C₂₋₆) carbon atoms, or a branched monovalent hydrocarbon radical of 3to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 12 (C₃₋₁₂), 3 to 10 (C₃₋₁₀), or 3to 6 (C₃₋₆) carbon atoms. Examples of alkynyl groups include, but arenot limited to, ethynyl (—C≡CH) and propargyl (—CH₂C≡CH). For example,C₂₋₆ alkynyl refers to a linear unsaturated monovalent hydrocarbonradical of 2 to 6 carbon atoms or a branched unsaturated monovalenthydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, thealkynyl is optionally substituted as described herein elsewhere.

As used herein, and unless otherwise specified, the term “aralkyl”refers to a monovalent alkyl group substituted with aryl. Aralkylincludes, but is not limited to, phenylmethyl (benzyl). In certainembodiments, both the alkyl and aryl portions may be optionallysubstituted with one or more substituents as described herein elsewhere.

As used herein, and unless otherwise specified, the term “aryl” refersto an optionally substituted monocyclic or multicyclic radical or ringsystem that contains at least one aromatic hydrocarbon ring. In certainembodiments, the aryl has from 6 to 20, from 6 to 15, or from 6 to 10ring atoms. Examples of aryl groups include, but are not limited to,phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl,biphenyl, and terphenyl. In certain embodiments, aryl may be bicyclic,tricyclic, or tetracyclic, where one of the rings is aromatic and theother(s) of the rings may be saturated, partially unsaturated, oraromatic, for example, dihydronaphthyl, indenyl, indanyl, ortetrahydronaphthyl (tetralinyl). In certain embodiments, aryl may be abicyclic, tricyclic, or tetracyclic ring system, where at least one ofthe rings is aromatic and one or more of the ring(s) is/are saturated orpartially unsaturated containing one or more heteroatoms independentlyselected from O, S. and N. In certain embodiments, the aryl isoptionally substituted with one or more substituents as described hereinelsewhere.

The terms “bicyclic” and “multicyclic” as used herein include fused,spirocyclic, and bridged bicyclic and multicyclic compounds.

As used herein, and unless otherwise specified, the term “cycloalkyl”refers to a cyclic fully or partially saturated bridged and/ornon-bridged hydrocarbon radical or ring system, which may be optionallysubstituted with one or more substituents. In certain embodiments, thecycloalkyl has from 3 to 20 (C₃₋₂₀), from 3 to 15 (C₃₋₁₅), from 3 to 12(C₃₋₁₂), from 3 to 10 (C₃₋₁₀), or from 3 to 7 (C₃₋₇) carbon atoms. Incertain embodiments, cycloalkyl may be a bicyclic, tricyclic, ortetracyclic ring system, where at least one of the rings is a cycloalkylring. Examples of cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,decalinyl, and adamantyl. In certain embodiments, the cycloalkyl isoptionally substituted as described herein elsewhere.

The term “haloalkyl” refers to an alkyl as defined above that issubstituted by one or more halo groups. In some embodiments, thehaloalkyl is monohaloalkyl, dihaloalkyl or polyhaloalkyl, includingperhaloalkyl. A monohaloalkyl can have one iodo, bromo, chloro or fluorowithin the alkyl group. Dihaloalkyl and polyhaloalkyl groups can havetwo or more of the same halo atoms or a combination of different halogroups within the alkyl. In some embodiments, the polyhaloalkyl containsup to 12 or or 8 or 6 or 4 or 3 or 2 halo groups. Representativeexamples of haloalkyl moieties include fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloromethyl anddichloropropyl.

A perhaloalkyl includes alkyl groups having all hydrogen atoms replacedwith halo atoms.

The term “halogen” or “halo” includes fluorine, bromine, chlorine, andiodine.

As used herein, and unless otherwise specified, the term “heteroalkyl”refers to a stable straight or branched chain (saturated orunsaturated), or cyclic hydrocarbon radical, or combinations thereof,consisting of the stated number of carbon atoms and at least one, suchas one to three, heteroatoms selected from O, N, Si, and S, and whereinthe nitrogen and sulfur atoms are optionally oxidized and the nitrogenheteroatom can optionally be quaternized. In certain embodiments, theheteroatom(s) may be placed at any interior position of the heteroalkylgroup. In certain embodiments, the heteroatom(s) may be placed at aterminal position, such as the position at which the alkyl group isattached to the remainder of the molecule. In certain embodiments wherean oxygen atom is at the terminal position where the alkyl group isattached to the remainder of the molecule, it is referred to as an“alkoxy” group. Examples of heteroalkyl include, but are not limited to,—CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃,—CH₂—CH₂—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃,—CH₂—CH═N—OCH₃, and —CH═CH—N(CH₃)—CH₃. Up to two heteroatoms can beconsecutive, such as, for example, —CH₂—NH—O—CH₃ and —CH₂—O—Si(CH₃)₃. Incertain embodiments, the heteroalkyl is optionally substituted asdescribed herein elsewhere.

The term “heteroaralkyl” as used herein refers to a monovalent alkylgroup substituted with heteroaryl. Heteroaralkyl includes, but is notlimited to, pyridylmethyl. In certain embodiments, both the alkyl andheteroaryl portions may be optionally substituted with one or moresubstituents as described herein elsewhere.

As used herein, and unless otherwise specified, the term “heteroaryl”refers to an optionally substituted monocyclic or multicyclic radical orring system which contains at least one aromatic ring having one or moreheteroatoms independently selected from O, S, and N. In certainembodiments, each ring of a heteroaryl group can contain one or two Oatoms, one or two S atoms, and/or one to four N atoms, provided that thetotal number of heteroatoms in each ring is four or less and each ringcontains at least one carbon atom. In certain embodiments, each ring ofa heteroaryl group can contain one O atom, one S atoms, and/or one tofour N atoms, provided that the total number of heteroatoms in each ringis four or less and each ring contains at least one carbon atom. Incertain embodiments, the heteroaryl has from 5 to 20, from 5 to 15, orfrom 5 to 10 ring atoms. In certain embodiments, heteroaryl also refersto bicyclic, tricyclic, or tetracyclic ring systems, where one of therings is aromatic having one or more heteroatoms independently selectedfrom O, S, and N, and the other(s) of the rings may be saturated,partially unsaturated, or aromatic and may be carbocyclic or contain oneor more heteroatoms independently selected from O, S, and N. Examples ofmonocyclic heteroaryl groups include, but are not limited to, furanyl,imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl,thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. Examples ofbicyclic heteroaryl groups include, but are not limited to,benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl,benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl,benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl,indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl,isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl,oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl,pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl,thiadiazolopyrimidyl, and thienopyridyl. Examples of tricyclicheteroaryl groups include, but are not limited to, acridinyl,benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl,phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl,phenoxazinyl, and xanthenyl. In certain embodiments, the heteroaryl isoptionally substituted with one or more substituents as described hereinelsewhere.

The term “heteroatom” includes atoms of any element other than carbon orhydrogen, including, but not limited to, nitrogen, oxygen and sulfur.

As used herein, and unless otherwise specified, the term“heterocycloalkyl” or “heterocyclyl” refers to an optionally substitutedmonocyclic or multicyclic radical or ring system which contains at leastone non-aromatic (saturated or partially saturated) ring having one ormore heteroatoms independently selected from O, S, and N. In certainembodiments, the heterocyclyl or heterocycloalkyl group has from 3 to20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6ring atoms. In certain embodiments, the heterocyclyl or heterocycloalkylis a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, andthe other(s) of the rings may be saturated, partially unsaturated, oraromatic and may be carbocyclic or contain one or more heteroatomsindependently selected from O, S, and N. In certain embodiments,nitrogen or sulfur atoms may be optionally oxidized and the nitrogenatoms may be optionally quaternized. The heterocycloalkyl orheterocyclyl may be attached to the remainder of the molecule at aheteroatom or a carbon atom. Examples include, but are not limited to,azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl,benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl,benzothiopyranyl, benzoxazinyl, β-carbolinyl, chromanyl, chromonyl,cinnolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl,dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl,dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl,furanonyl, imidazolidinyl, imidazolinyl, indolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl,isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl,oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl,pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl,tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl,tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl,and 1,3,5-trithianyl. In certain embodiments, the heterocyclyl orheterocycloalkyl is optionally substituted with one or more substituentsas described herein elsewhere.

As used herein, and unless otherwise specified, the terms “optionallysubstituted” and “substituted” are intended to mean that a group,including, but not limited to, alkyl, alkenyl, alkynyl, cycloalkyl,heteroalkyl, alkoxy, aryl, aralkyl, heteroaralkyl, heteroaryl, orheterocyclyl, may be substituted with one or more substituentsindependently selected from, e.g., (a) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, andheterocyclyl, each optionally substituted with one or more, in oneembodiment, one, two, three, or four, substituents Q¹; and (b) halo,cyano (—CN), nitro (—NO₂), oxo (═O), —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a),—OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a),—OS(O)₂R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c),—NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c),—NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d),—NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a),—S(O)₂R^(a), —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein eachR^(a), R^(b), R^(c), and R^(d) is independently (i) hydrogen; (ii) C₁₋₆alkyl, C₂₋₄ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl, each optionally substituted withone or more, in one embodiment, one, two, three, or four, substituentsQ¹; or (iii) R^(b) and R^(c) together with the N atom to which they areattached form heteroaryl or heterocyclyl, optionally substituted withone or more, in one embodiment, one, two, three, or four, substituentsQ¹. As used herein, all groups that can be substituted are “optionallysubstituted,” unless otherwise specified.

In one embodiment, each Q¹ is independently selected from (a) cyano,halo, oxo, and nitro; and (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, andheterocyclyl; and (c) —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g),—C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e), —OC(O)OR^(e),—OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(e)C(O)R^(h),—NR^(e)C(O)OR^(f)R^(g), —NR^(e)C(O)NR^(f)R^(g),—NR^(e)C(═NR^(h))NR^(f)R^(g), —NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h),—NR^(e)S(O)NR^(f)R^(g), —NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e),—S(O)₂R^(e), —S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein eachR^(e), R^(f), R^(g), and R^(h) is independently (i) hydrogen; (ii) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (iii) R^(f) and R^(g) togetherwith the N atom to which they are attached form heteroaryl orheterocyclyl.

It will be noted that the structure of some of the compounds of thisinvention include asymmetric carbon atoms. It is to be understoodaccordingly that the stereoisomers arising from such asymmetry (e.g.,all enantiomers and diastereomers) are included within the scope of thisinvention, unless indicated otherwise. Furthermore, the structures andother compounds and moieties discussed in this application also includeany tautomers or geometric isomers (e.g., cis/trans or E/Z) thereof.Accordingly, a compound of the present invention may be in the form ofone of the possible isomers, rotamers, atropisomers, tautomers ormixtures thereof, for example, as substantially pure geometric (e.g.,cis or trans) isomers, diastereomers, optical isomers (e.g., antipodes),racemates or mixtures thereof.

As used herein, and unless otherwise specified, the term “solvate”refers to a compound provided herein or a salt thereof, which furtherincludes a stoichiometric or non-stoichiometric amount of solvent boundby non-covalent intermolecular forces. Where the solvent is water, thesolvate is a hydrate.

As used herein, and unless otherwise specified, the term “stereoisomer”encompasses all enantiomerically/stereomerically pure andenantiomerically/stereomerically enriched compounds provided herein.

As used herein and unless otherwise specified, the term “stereomericallypure” means a composition that comprises one stereoisomer of a compoundand is substantially free of other stereoisomers of that compound. Forexample, a stereomerically pure composition of a compound having onechiral center will be substantially free of the opposite enantiomer ofthe compound. A stereomerically pure composition of a compound havingtwo or more chiral centers is substantially free of other diastereomers.A typical stereomerically pure compound comprises greater than about 80%by weight of one stereoisomer, greater than about 90% by weight of onestereoisomer, greater than about 95% by weight of one stereoisomer,greater than about 97% by weight of one stereoisomer, greater than about99% by weight, greater than 99.5%, or even greater than 99.9% of onestereoisomer.

In describing an optically active compound, the prefixes R and S areused to denote the absolute configuration of the molecule about itschiral center(s). The (+) and (−) notations are used to denote theoptical rotation of the compound, that is, the direction in which aplane of polarized light is rotated by the optically active compound.The (−) prefix indicates that the compound is levorotatory, that is, thecompound rotates the plane of polarized light to the left orcounterclockwise. The (+) prefix indicates that the compound isdextrorotatory, that is, the compound rotates the plane of polarizedlight to the right or clockwise. However, the sign of optical rotation,(+) and (−), is not related to the absolute configuration of themolecule, R and S.

As used herein, and unless otherwise indicated, the terms “treat,”“treating” and “treatment” refer to the eradication or amelioration of adisease or disorder, or of one or more symptoms associated with thedisease or disorder. In certain embodiments, the terms refer tominimizing the spread or worsening of the disease or disorder resultingfrom the administration of one or more prophylactic or therapeuticagents to a subject with such a disease or disorder. In someembodiments, the terms refer to the administration of a compoundprovided herein, with or without other additional active agent(s), afterthe onset of symptoms of the particular disease (e.g., adjuctive orcombination therapy).

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment or management of a disease ordisorder, or to delay or minimize one or more symptoms associated withthe disease or disorder. A therapeutically effective amount of acompound means an amount of therapeutic agent, alone or in combinationwith other therapies, which provides a therapeutic benefit in thetreatment or management of the disease or disorder. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease ordisorder, or enhances the therapeutic efficacy of another therapeuticagent.

As used herein, and unless otherwise specified, the term“pharmaceutically acceptable salts” refers to salts prepared frompharmaceutically acceptable non-toxic acids, including inorganic acidsand organic acids; or from pharmaceutically acceptable non-toxic bases,including inorganic bases and organic bases. In one embodiment, suitablenon-toxic acids include, but are not limited to, acetic, alginic,anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethenesulfonic, formic, fumaric, furoic, gluconic, glutamic, glucorenic,galacturonic, glycidic, hydrobromic, hydrochloric, isethionic, lactic,maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic,pantothenic, phenylacetic, propionic, phosphoric, salicylic, stearic,succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic.

Any formula given herein is also intended to include unlabeled forms aswell as isotopically labeled forms of the compounds. For example, anyhydrogen represented by “H” in the formulae herein is intended torepresent all isotopic forms of hydrogen (e.g., ¹H, ²H or D, or ³H or T)unless otherwise specified; any carbon represented in any of theformulae disclosed herein are intended to represent all isotopic formsof carbon (e.g., ¹¹C, ¹³C, ¹⁴C) unless otherwise specified; similarly,any nitrogen represented by “N” is intended to represent all isotopicforms of nitrogen (e.g., ¹⁴N, ¹⁸N) unless otherwise specified.Enrichment with heavier isotopes, particularly deuterium (i.e., ²H or D)may afford certain therapeutic advantages including, but not limited to,greater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index.Other examples of isotopes include, but are not limited to, oxygen,sulfur, phosphorous, fluorine, iodine and chlorine, such as ¹⁸F, ¹⁵O,³¹P, ³²P, ³⁵S, ³⁶Cl and ¹²⁵I. The invention includes variousisotopically labeled compounds as defined herein, for example those intowhich radioactive isotopes, such as ³H, ¹³C and ¹⁴C are present. In someembodiments, the atoms in the formulae herein occur in their naturalabundance. In some embodiments, one or more hydrogen atom may beenriched in ²H; or/and one or more carbon atom may be enriched in ¹¹C,¹³C or ¹⁴C; or/and one or more nitrogen may be enriched in ¹⁴N.

Isotopically labeled compounds of this invention can generally beprepared by carrying out the procedures disclosed in the schemes or inthe examples and preparations described below by substituting a readilyavailable isotopically labeled reagent for a non-isotopically labeledreagent.

It should be noted that if there is a discrepancy between a depictedstructure and a chemical name given that structure, the depictedstructure is to be accorded more weight.

Neurological Diseases and Disorders

As used herein, and unless otherwise specified, the term “neurologicaldisorder” includes diseases, disorders or conditions of the central orperipheral nervous system of a mammal. The term “neurological disorder”includes, but is not limited to, neurodegenerative diseases,neuropsychiatric diseases, affective disorders, and loss of cognitivefunction, learning and memory disorders. The term “neurologicaldisorder” also includes conditions associated with the disorder. Forinstance, a method of treating a neurodegenerative disorder includesmethods of treating loss of memory and/or loss of cognition associatedwith a neurodegenerative disorder. The term “neurological disorder” alsoincludes diseases or conditions that are implicated, at least in part,in monoamine (e.g., norepinephrine) signaling pathways (e.g.,cardiovascular disease).

Neurodegenerative Diseases and Disorders

The term “neurodegenerative disease” includes diseases and disordersthat are associated with the progressive loss of structure or functionof neurons, or death of neurons. Neurodegenerative diseases anddisorders include, but are not limited to, Alzheimer's disease(including the associated symptoms of mild, moderate, or severecognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic andischemic injuries; ataxia and convulsion (including for the treatmentand prevention and prevention of seizures that are caused byschizoaffective disorder or by drugs used to treat schizophrenia);benign forgetfulness; brain edema; cerebellar ataxia including McLeodneuroacanthocytosis syndrome (MLS); closed head injury; coma; contusiveinjuries (e.g., spinal cord injury and head injury); dementias includingmulti-infarct dementia and senile dementia; disturbances ofconsciousness; Down syndrome; drug-induced or medication-inducedParkinsonism (such as neuroleptic-induced acute akathisia, acutedystonia, Parkinsonism, or tardive dyskinesia, neuroleptic malignantsyndrome, or medication-induced postural tremor); epilepsy; fragile Xsyndrome; Gilles de la Tourette's syndrome; head trauma; hearingimpairment and loss; Huntington's disease; Lennox syndrome;levodopa-induced dyskinesia; mental retardation; movement disordersincluding akinesias and akinetic (rigid) syndromes (including basalganglia calcification, corticobasal degeneration, multiple systematrophy, Parkinsonism-ALS dementia complex, Parkinson's disease,postencephalitic parkinsonism, and progressively supranuclear palsy);muscular spasms and disorders associated with muscular spasticity orweakness including chorea (such as benign hereditary chorea,drug-induced chorea, hemiballism, Huntington's disease,neuroacanthocytosis, Sydenham's chorea, and symptomatic chorea),dyskinesia (including tics such as complex tics, simple tics, andsymptomatic tics), myoclonus (including generalized myoclonus and focalcyloclonus), tremor (such as rest tremor, postural tremor, and intentiontremor) and dystonia (including axial dystonia, dystonic writer's cramp,hemiplegic dystonia, paroxymal dystonia, and focal dystonia such asblepharospasm, oromandibular dystonia, and spasmodic dysphonia andtorticollis); neuronal damage including ocular damage, retinopathy ormacular degeneration of the eye; neurotoxic injury which followscerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebralischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia,perinatal asphyxia and cardiac arrest; Parkinson's disease; seizure;status epilecticus; stroke; tinnitus; tubular sclerosis; and viralinfection induced neurodegeneration (e.g., caused by acquiredimmunodeficiency syndrome (AIDS) and encephalopathics).Neurodegenerative diseases also include, but are not limited to,neurotoxic injury which follows cerebral stroke, thromboembolic stroke,hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia,amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest. Methodsof treating or preventing a neurodegenerative disease also includetreating or preventing loss of neuronal function characteristic ofneurodegenerative disorder.

Neuropsychiatric Diseases and Disorders

The term “neuropsychiatric disease” includes those neuropsychiatricdiseases and disorders set forth in The Diagnostic and StatisticalManual of Mental Disorders, Revised, Fourth Ed., (DSM-IV-R), publishedby the American Psychiatric Association, which is incorporated herein byreference. Such disorders include, but are not limited to, aggression;attention disorders including attention-deficit disorder (ADD),attention-deficit-hyperactivity disorder (ADHD) and conduct disorder,delirium; delusional disorder, persisting dementia; pervasivedevelopment disorder including autism, autistic disorder and autismspectrum disorder psychosis and psychotic disorders (including psychosisassociated with affective disorders, brief reactive psychosis, briefpsychotic disorder, shared psychotic disorder, and psychotic disorderdue to a general medical condition and substance-induced or drug-inducedpsychotic disorder (e.g., caused by phencyclidine, ketamine and otherdissociative anaesthetics, amphetamine, cocaine and otherpsychostimulants)); schizophrenia (including schizoaffective psychosisand “schizophrenia-spectrum” disorders such as schizoid or schizotypalpersonality disorders, or illnesses associated with psychosis (such asmajor depression, manic depressive (bipolar) disorder, Alzheimer'sdisease and post-traumatic stress syndrome) including both the positiveand negative symptoms of schizophrenia and other psychoses); and sensoryhyper-excitability.

The terms “attention deficit disorder” (ADD), “attention deficitdisorder with hyperactivity (ADDH),” and “attentiondeficit/hyperactivity disorder” (AD/HD), are used herein in accordancewith the accepted meanings as found in the Diagnostic and StatisticalManual of Mental Disorders, 4th Ed., American Psychiatric Association(DSM-IV™-R). ADD and ADHD include disorders that are most prevalent inchildren and are associated with increased motor activity and adecreased attention span that may result in inappropriate actions inlearning and social situations.

The term “psychosis” includes mental states in which a subject sufferingfrom psychosis undergoes a loss of contact with reality. Symptoms ofpyschosis include hallucinations, delusions and impaired sight. In someembodiments, the psychosis may be associated with anotherneuropsychiatric disorder, for example, schizophrenia, schizophreniformdisorder, schizoaffective disorder, brief psychotic disorder, bipolardisorder, clinical depression, psychosocial disorder. In someembodiments, the psychosis is related to general medical conditions, forexample, brain tumors, brain damage, an epileptic disorder, dementia,multiple sclerosis, Lyme disease, Alzheimer's disease, Parkinson'sdisease, electrolyte disorders, hypoglycemia and AIDS. In someembodiments, the psychosis is substance-induced psychosis.

The term “schizophrenia” includes a mental disorders characterized bythe disintegration of the process of thinking and emotionalresponsiveness, and includes symptoms such as auditory hallucinations,paranoid delusions, disorganized speech, disorganized thinking, andextensive withdrawal of the patient's interests from other people. Theterm “schizophrenia” also includes schizophreniform disorder andschizoaffective disorder. So-called negative symptoms of schizophreniainclude affect blunting, anergia, alogia and social withdrawal. Positivesymptoms of schizophrenia include delusion and hallucination. Cognitivesymptoms of schizophrenia include impairment in obtaining, organizing,and using intellectual knowledge.

Affective Disorders

As used herein, and unless otherwise specified, the term “affectivedisorder” includes agoraphobia; anxiety and anxiety disorders (includingbut not limited to acute stress disorder, anxiety due to a generalmedical condition, dental phobia, generalized anxiety disorder, panicdisorder, separation anxiety disorder, social anxiety disorder, socialphobia, specific phobia, and substance-induced anxiety disorder);bipolar disorders; depression (including but not limited to dysthymia,major depressive disorder, seasonal affective disorder, seasonaldepression, unipolar depression, and post-partum depression); fatigueassociated with depression including but limited to chronic fatiguesyndrome; mood disorders (including disorders due to a general medicalcondition and substance-induced mood-disorders); obsessive-compulsivedisorder, panic attack; perimenopause, menopause, and male menopause;post-traumatic stress disorder, premenstrual syndrome (PMS) andpremenstrual dysphoric disorder (PDD); and sleep disorders includinginsomnia and narcolepsy.

Cognitive Function, Learning, and Memory Disorders

As used herein, and unless otherwise specified, the terms “cognitivedysfunction,” “cognitive function disorder,” “learning disorder”, and“memory disorder” apply to disorders that may be treated by improvingmammalian brain function. The terms include disorders in which subjectsexhibit symptoms of memory or learning loss, have impaired ability tolearn new information or to recall previously learned information orpast efforts. In some embodiments, these disorders cause markedimpairment in social or occupational functioning and represent asignificant decline from a previous level of functions. In someembodiments, the cognitive dysfunction may be associated with, forexample, adult and childhood learning disorders; altruism; amnesticdisorders (including Alzheimer's disease-related cognitive decline,normal age-related cognitive decline and persisting amnestic disorder);associative learning; attention; benign forgetfulness; cognitivedeficits induced by situational stress (including but not limited tooperating machinery for extended time periods or working in emergency orcombat situations); cognitive disorders including dementia (associatedwith acquired immunodeficiency disease, Alzheimer's disease,Creutzfeldt-Jacob disease, HIV infection, Huntington's disease,ischemia, multi-infarct dementia, Parkinson's disease, perinatalhypoxia, Pick's disease, trauma, vascular problems or stroke, othergeneral medical conditions or substance abuse); cooperativity;declarative memory; early consolidation; empathy; episodic memory;executive function; explicit memory; implicit memory; imprinting;language; late consolidation; learning (including electronic, formal,informal, multimedia and rote learning); low IQ; memory deficit; memoryloss; mild cognitive impairment (MCI); non-verbal and verbalcommunicative skills; play; rehearsal; retrieval, semantic memory;sensory integration of environmental cues including temperature, odor,sounds, touch, and taste; social cognition; and speech disorders.

Substance Abuse and Eating Disorders

The term “substance abuse” includes a pattern of behavior in which asubject uses a substance in an abusive manner and is used herein in amanner consistent with its accepted meaning in the art. (See, e.g.,DSM-IV™.) Examples of substance abuse include abuse of or addiction tocannabis, cocaine, morphine, opioids, nicotine, or alcohol;substance-abuse related disorders and addictive behaviors (includingsubstance-induced delirium); tolerance, dependence or withdrawal fromsubstances including alcohol, amphetamines, anxiolytics, cannabis,cocaine, hallucinogens, hypnotics, inhalants, nicotine, opioids,phencyclidine, or sedatives.

The term “eating disorder,” as used herein, refers to abnormalcompulsions to avoid eating or uncontrollable impulses to consumeabnormally large amounts of food. Eating disorders include, but are notlimited to, anorexia nervosa, binge eating, bulimia nervosa, cachexia,compulsive eating disorder, emesis, and obesity.

Pain

As used herein, and unless otherwise specified, the term “pain” refersto an unpleasant sensory and emotional experience. The term “pain,” asused herein, refers to all categories of pain, including pain that isdescribed in terms of stimulus or nerve response, e.g., somatic pain(normal nerve response to a noxious stimulus) and neuropathic pain(abnormal response of a injured or altered sensory pathway, oftenwithout clear noxious input); pain that is categorized temporally, e.g.,chronic pain and acute pain; pain that is categorized in terms of itsseverity, e.g., mild, moderate, or severe; and pain that is a symptom ora result of a disease state or syndrome, e.g., inflammatory pain, cancerpain, carpal tunnel syndrome, AIDS pain, arthropathy, migraine,trigeminal neuralgia, cardiac ischaemia, neuropathy arising from chronicalcohol use, and diabetic peripheral neuropathic pain (see, e.g.,Harrison's Principles of Internal Medicine, pp. 93-98 (Wilson et al.,eds., 12th ed. 1991); Williams et al., J. of Med. Chem. 42: 1481-1485(1999), herein each incorporated by reference in their entirety). “Pain”is also meant to include mixed etiology pain, dual mechanism pain,allodynia, causalgia, central pain, hyperesthesia, hyperpathia,dysesthesia, and hyperalgesia. In addition, the term “pain” includespain resulting from dysfunction of the nervous system: organic painstates that share clinical features of neuropathic pain and possiblecommon pathophysiology mechanisms, but are not initiated by anidentifiable lesion in any part of the nervous system.

The term “somatic pain,” as used herein, refers to a normal nerveresponse to a noxious stimulus such as injury or illness, e.g., trauma,burn, infection, inflammation, or disease process such as cancer, andincludes both cutaneous pain (e.g., skin, muscle or joint derived) andvisceral pain (e.g., organ derived).

The term “neuropathic pain,” as used herein, refers to a heterogeneousgroup of neurological conditions that result from damage to the nervoussystem. The term also refers to pain resulting from injury to ordysfunctions of peripheral and/or central sensory pathways, and fromdysfunctions of the nervous system, where the pain often occurs orpersists without an obvious noxious input. This includes pain related toperipheral neuropathies as well as central neuropathic pain. Commontypes of peripheral neuropathic pain include diabetic neuropathy (alsocalled diabetic peripheral neuropathic pain, or DN, DPN, or DPNP),post-herpetic neuralgia (PHN), and trigeminal neuralgia (TGN). Centralneuropathic pain, involving damage to the brain or spinal cord, canoccur following stroke, spinal cord injury, and as a result of multiplesclerosis, and is also encompassed by the term. Other types of pain thatare meant to be included in the definition of neuropathic pain include,but are not limited to, pain from neuropathic cancer pain, HIV/AIDSinduced pain, phantom limb pain, and complex regional pain syndrome.

The term also encompasses the common clinical features of neuropathicpain including, but not limited to, sensory loss, allodynia (non-noxiousstimuli produce pain), hyperalgesia and hyperpathia (delayed perception,summation, and painful after sensation). Pain is often a combination ofnociceptive and neuropathic types, for example, mechanical spinal painand radiculopathy or myelopathy.

As used herein, and unless otherwise specified, the term “acute pain”refers to the normal, predicted physiological response to a noxiouschemical, thermal or mechanical stimulus typically associated withinvasive procedures, trauma and disease. It is generally time-limited,and may be viewed as an appropriate response to a stimulus thatthreatens and/or produces tissue injury. The term also refers to painwhich is marked by short duration or sudden onset.

As used herein, and unless otherwise specified, the term “chronic pain”encompasses the pain occurring in a wide range of disorders, forexample, trauma, malignancies and chronic inflammatory diseases such asrheumatoid arthritis. Chronic pain may last more than about six months.In addition, the intensity of chronic pain may be disproportionate tothe intensity of the noxious stimulus or underlying process. The termalso refers to pain associated with a chronic disorder, or pain thatpersists beyond resolution of an underlying disorder or healing of aninjury, and that is often more intense than the underlying process wouldpredict. It may be subject to frequent recurrence.

As used herein, and unless otherwise specified, the term “inflammatorypain” is pain in response to tissue injury and the resultinginflammatory process. Inflammatory pain is adaptive in that it elicitsphysiologic responses that promote healing. However, inflammation mayalso affect neuronal function. Inflammatory mediators, including PGE2induced by the COX2 enzyme, bradykinins, and other substances, bind toreceptors on pain-transmitting neurons and alter their function,increasing their excitability and thus increasing pain sensation. Muchchronic pain has an inflammatory component. The term also refers to painwhich is produced as a symptom or a result of inflammation or an immunesystem disorder.

As used herein, and unless otherwise specified, the term “visceral pain”refers to pain which is located in an internal organ.

As used herein, and unless otherwise specified, the term “mixed etiologypain” refers to pain that contains both inflammatory and neuropathiccomponents.

As used herein, and unless otherwise specified, the term “dual mechanismpain” refers to pain that is amplified and maintained by both peripheraland central sensitization.

As used herein, and unless otherwise specified, the term “causalgia”refers to a syndrome of sustained burning, allodynia, and hyperpathiaafter a traumatic nerve lesion, often combined with vasomotor andsudomotor dysfunction and later trophic changes.

As used herein, and unless otherwise specified, the term “central pain”refers to pain initiated by a primary lesion or dysfunction in thecentral nervous system.

As used herein, and unless otherwise specified, the term “hyperesthesia”refers to increased sensitivity to stimulation, excluding the specialsenses.

As used herein, and unless otherwise specified, the term “hyperpathia”refers to a painful syndrome characterized by an abnormally painfulreaction to a stimulus, especially a repetitive stimulus, as well as anincreased threshold. It may occur with allodynia, hyperesthesia,hyperalgesia, or dysesthesia.

As used herein, and unless otherwise specified, the term “dysesthesia”refers to an unpleasant abnormal sensation, whether spontaneous orevoked. In certain embodiments, dysesthesia include hyperalgesia andallodynia.

As used herein, and unless otherwise specified, the term “hyperalgesia”refers to an increased response to a stimulus that is normally painful.It reflects increased pain on suprathreshold stimulation.

As used herein, and unless otherwise specified, the term “allodynia”refers to pain due to a stimulus that does not normally provoke pain.

As used herein, and unless otherwise specified, the term “DiabeticPeripheral Neuropathic Pain” (DPNP), also called diabetic neuropathy, DNor diabetic peripheral neuropathy), refers to chronic pain caused byneuropathy associated with diabetes mellitus. The classic presentationof DPNP is pain or tingling in the feet that can be described not onlyas “burning” or “shooting” but also as severe aching pain. Lesscommonly, patients may describe the pain as itching, tearing, or like atoothache. The pain may be accompanied by allodynia and hyperalgesia andan absence of symptoms, such as numbness.

As used herein, and unless otherwise specified, the term “Post-HerpeticNeuralgia”, also called “Postherpetic Neuralgia (PHN)”, refers to apainful condition affecting nerve fibers and skin. Without being limitedby a particular theory, it is a complication of shingles, a secondoutbreak of the varicella zoster virus (VZV), which initially causeschickenpox.

As used herein, and unless otherwise specified, the term “neuropathiccancer pain” refers to peripheral neuropathic pain as a result ofcancer, and can be caused directly by infiltration or compression of anerve by a tumor, or indirectly by cancer treatments such as radiationtherapy and chemotherapy (chemotherapy-induced neuropathy).

As used herein, and unless otherwise specified, the term “HIV/AIDSperipheral neuropathy” or “HIV/AIDS related neuropathy” refers toperipheral neuropathy caused by HIV/AIDS, such as acute or chronicinflammatory demyelinating neuropathy (AIDP and CIDP, respectively), aswell as peripheral neuropathy resulting as a side effect of drugs usedto treat HIV/AIDS.

As used herein, and unless otherwise specified, the term “Phantom LimbPain” refers to pain appearing to come from where an amputated limb usedto be. Phantom limb pain can also occur in limbs following paralysis(e.g., following spinal cord injury). “Phantom Limb Pain” is usuallychronic in nature.

As used herein, and unless otherwise specified, the term “TrigeminalNeuralgia (TN)” refers to a disorder of the fifth cranial (trigeminal)nerve that causes episodes of intense, stabbing, electric-shock-likepain in the areas of the face where the branches of the nerve aredistributed (lips, eyes, nose, scalp, forehead, upper jaw, and lowerjaw). It is also known as the “suicide disease”.

As used herein, and unless otherwise specified, the term “ComplexRegional Pain Syndrome (CRPS),” formerly known as Reflex SympatheticDystrophy (RSD), refers to a chronic pain condition whose key symptom iscontinuous, intense pain out of proportion to the severity of theinjury, which gets worse rather than better over time. The termencompasses type 1 CRPS, which includes conditions caused by tissueinjury other than peripheral nerve, and type 2 CRPS, in which thesyndrome is provoked by major nerve injury, and is sometimes calledcausalgia.

As used herein, and unless otherwise specified, the term “fibromyalgia”refers to a chronic condition characterized by diffuse or specificmuscle, joint, or bone pain, along with fatigue and a range of othersymptoms. Previously, fibromyalgia was known by other names such asfibrositis, chronic muscle pain syndrome, psychogenic rheumatism andtension myalgias.

As used herein, and unless otherwise specified, the term “convulsion”refers to a neurological disorder and is used interchangeably with“seizure,” although there are many types of seizure, some of which havesubtle or mild symptoms instead of convulsions. Seizures of all typesmay be caused by disorganized and sudden electrical activity in thebrain. In some embodiments, convulsions are a rapid and uncontrollableshaking during which the muscles contract and relax repeatedly.

Pharmaceutical Compositions

In certain embodiments, the present invention provides a pharmaceuticalcomposition comprising a compound as disclosed herein and apharmaceutically acceptable carrier.

The term “pharmaceutically acceptable carrier” includes any and allsolvents, dispersion media, coatings, surfactants, antioxidants,preservatives (e.g., antibacterial agents, antifungal agents), isotonicagents, absorption delaying agents, salts, preservatives, drugs, drugstabilizers, binders, excipients, disintegration agents, lubricants,sweetening agents, flavoring agents, dyes, such like materials andcombinations thereof, as would be known to one of ordinary skill in theart (see, for example, Remington's Pharmaceutical Sciences, 18th Ed.Mack Printing Company, 1990, pp. 1289-1329). Except insofar as anyconventional carrier is incompatible with the active ingredient, its usein the therapeutic or pharmaceutical compositions is contemplated by theinvention.

The pharmaceutical composition may be formulated for particular routesof administration such as oral, intravenous, intraperitoneal,parenteral, enteral, sublingual, vaginal, subcutaneous, transdermal,transmucosal, sublabial, buccal, intracerebral, intracerebroventricular,intramuscular, intranasal, intrathecal, inhalation, topical, or rectaladministration, etc. In addition, the pharmaceutical compositions of thepresent invention may be in a solid form including capsules, tablets,pills, granules, powders, thin film, or suppositories, or in a liquidform including solutions, suspensions, gels, creams, or emulsions. Thepharmaceutical compositions may be subjected to conventionalpharmaceutical operations such as sterilization and/or can containconventional inert diluents, lubricating agents or buffering agents, aswell as adjuvants, such as preservatives, stabilizers, wetting agents,emulsifiers and buffers.

In some embodiments, the pharmaceutical compositions are tablets orgelatin capsules comprising the active ingredient together with a)diluents, (e.g., lactose, dextrose, sucrose, mannitol, sorbitol,cellulose and/or glycine); b) lubricants, (e.g., silica, talcum, stearicacid, its magnesium or calcium salt and/or polyethyleneglycol); c)binders, (e.g., magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrrolidone); d) disintegrants, (e.g., starches, agar, alginicacid or its sodium salt, or effervescent mixtures); or c) absorbents,colorants, flavors and sweeteners; or any combination thereof.

Tablets may be either film coated or enteric coated according to methodsknown in the art.

Suitable compositions for oral administration include an effectiveamount of a compound as disclosed herein in the form of tablets,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsion, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use are prepared according to any method known in theart for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from sweeteningagents, flavoring agents, coloring agents and preservatives. Tabletsgenerally contain the active ingredient(s) in admixture with nontoxicpharmaceutically acceptable excipients that are suitable for themanufacture of tablets. These excipients are, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets may be uncoated or coated byknown techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. Formulations fororal use may be presented as hard gelatin capsules in which the activeingredient(s) are mixed with an inert solid diluent, for example,calcium carbonate, calcium phosphate or kaolin, or as soft gelatincapsules wherein the active ingredient is mixed with water or an oilmedium, for example, peanut oil, liquid paraffin or olive oil.

Certain injectable compositions are aqueous isotonic solutions orsuspensions, and suppositories may be prepared from fatty emulsions orsuspensions. Such compositions may be sterilized and/or containadjuvants, such as preserving, stabilizing, wetting or emulsifyingagents, solution promoters, salts for regulating the osmotic pressureand/or buffers. In addition, they may also contain other therapeuticagents. Such compositions may be prepared according to conventionalmixing, granulating or coating methods, respectively, and contain about0.1-75%, or contain about 1-50%, of the active ingredient.

Suitable compositions for transdermal application include an effectiveamount of a compound as disclosed herein with a carrier. Carriersinclude absorbable pharmacologically acceptable solvents to assistpassage through the skin of the subject. For example, transdermaldevices may be in the form of a bandage comprising a backing member, areservoir containing the compound optionally with carriers, optionally arate controlling barrier to deliver the compound of the skin of the hostat a controlled and predetermined rate over a prolonged period of time,and means to secure the device to the skin.

Suitable compositions for topical application, (e.g., to the skin andeyes), include aqueous solutions, suspensions, ointments, creams, gelsor sprayable formulations, (e.g., for delivery by aerosol and the like).Such topical compositions may contain solubilizers, stabilizers,tonicity enhancing agents, buffers and preservatives.

Topical application may also pertain to an inhalation or to anintranasal application. Such compositions may be delivered in the formof a dry powder (either alone, as a mixture, for example, a dry blendwith lactose, or a mixed component particle, for example withphospholipids) from a dry powder inhaler or an aerosol spraypresentation from a pressurized container, pump, spray, atomizer ornebuliser, with or without the use of a suitable propellant.

The present invention further provides anhydrous pharmaceuticalcompositions and dosage forms comprising a compound as disclosed hereinas active ingredient(s), since water may facilitate the degradation ofcertain compounds. Anhydrous pharmaceutical compositions and dosageforms of the invention may be prepared using anhydrous or low moisturecontaining ingredients and low moisture or low humidity conditions. Ananhydrous pharmaceutical composition may be prepared and stored suchthat its anhydrous nature is maintained. Accordingly, anhydrouscompositions are preferably packaged using materials known to preventexposure to water such that they can be included in suitable formularykits. Examples of suitable packaging include hermetically sealed foils,plastics, unit dose containers (e.g., vials), blister packs, and strippacks.

The invention further provides pharmaceutical compositions and dosageforms that comprise one or more agents that reduce the rate by which acompound as disclosed herein will decompose. Such agents, referred toherein as “stabilizers,” include antioxidants such as ascorbic acid, pHbuffers, or salt buffers, etc.

The pharmaceutical composition or combination of the present inventionmay be present in a unit dosage in an amount of about 0.001 mg-10 g,0.01-500 mg or about 0.01-250 mg or about 0.01-150 mg or about 0.01-100mg, or about 0.01-50 mg of active ingredient for a subject of about50-70 kg. The therapeutically effective dosage of a compound, thepharmaceutical composition, or the combinations thereof, is dependent onthe species of the subject, the body weight, age and individualcondition, the disorder or disease or the severity thereof beingtreated. A physician, clinician or veterinarian of ordinary skill canreadily determine the effective amount of each of the active ingredientsnecessary to prevent, treat or inhibit the progress of the disorder ordisease.

A therapeutically effective amount in vivo may range depending on theroute of administration, between about 0.0001-500 mg/kg, or betweenabout 0.0001-100 mg/kg, or between about 0.0003-10 mg/kg.

Methods of Treatment. Prevention, and/or Management

Binding to mGluR5 Receptor

In various embodiments, a method of binding a compound as disclosedherein to a metabotropic glutamate receptor, such as mGluR5 is provided.The method comprises contacting mGluR5 with an amount of compound asdisclosed herein effective to bind a metabotropic glutamate receptor.

In one embodiment, a method of modulating the activity of mGluR5 via thebinding of an mGluR5 ligand to mGluR5 is provided. The method comprisescontacting mGluR5 with an amount of a compound as disclosed hereineffective to modulate the activity of mGluR5. In one embodiment, theligand is L-glutamate. In another embodiment, the ligand is a drugmolecule or another small molecule known to have binding affinity tomGluR5. In another embodiment, the mGluR5 ligand is a radioactivelylabeled compound, known to bind to mGluR5. In other embodiments, bindingto metabotropic glutamate receptor may be assessed using PET imaging asis known in the art, e.g. utilizing appropriate PET ligands. In someembodiments, the ligand is an allosteric modulator (e.g., a positive ornegative allosteric modulator), antagonist, or inverse agonist ofmGluR5.

Modulation of mGluR5 Receptor Activity

In various embodiments, a method of modulating (e.g., inhibiting oraugmenting) the activity of a metabotropic glutamate receptor, such asmGluR5 is provided. The method comprises contacting the receptor, suchas mGluR5, with an amount of a compound as disclosed herein, or apharmaceutically acceptable salt thereof effective to modulate theactivity of a metabotropic glutamate receptor, in vitro or in vivo. Incertain embodiments, mGluR5 is contacted with a compound as disclosedherein by administering to a subject a therapeutically effective amountof a compound as disclosed herein, or a pharmaceutically acceptable saltor solvate thereof. In certain embodiments, the subject may be a mammal,such as a human, dog, monkey, baboon, rat, or mouse, preferably a human.

In certain embodiments, a compound as disclosed herein increases oraugments the activity of metabotropic glutamate receptor, such asmGluR5. In some embodiments, the activity of mGluR5 is increased oraugmented in the presence or absence of an mGluR5 ligand (e.g.,glutamate) by about 1%, about 5%, about 10%, about 20%, about 30%, about40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%,about 99% or more, as compared with the activity obtained in the absenceof a compound as disclosed herein. In certain such embodiments acompound as disclosed herein will not increase or augment the activityof mGluR5 in the absence of glutamate. In certain embodiments, theincrease or augmentation of receptor activity is dose-dependent.Increase of mGluR5 activity may be measured using assays known in theart, for example, by in vitro functional assays as described hereinelsewhere. In certain embodiments, the functional assay utilizes anappropriate cell-line expressing the desired metabotropic glutamatereceptor, such as mGluR5. In other embodiments, the functional assayutilizes synaptosomes isolated from brain tissue of an appropriateorganism. In other embodiments, inhibition of metabotropic glutamatereceptor activity may be assessed using receptor binding experimentsknown in the art, e.g., utilizing appropriate membrane preparations. Incertain embodiments, the assay involves treatment of a test subject(e.g., a mouse or a rat) with a compound as disclosed herein as well asa reference compound, followed by isolation of brain tissue and ex vivoanalysis of receptor occupancy. In certain embodiments, the mGluR5modulator is a positive allosteric modulator.

In certain embodiments, methods of increasing or augmenting the activityof a metabotropic glutamate receptor, such as mGluR5 in the presence orabsence of glutamate, in a subject (e.g., human) comprisingadministering to the subject an effective amount of compound asdisclosed herein are provided. In some embodiments, the activity ofmGluR5 is increased or augmented by about 1%, about 5%, about 10%, about20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%,about 90%, about 95%, about 99% or more, when measured using an assayknown in the art compared to the activity obtained in the absence ofadministration of a compound as disclosed herein.

In certain embodiments, a method of increasing or augmenting theactivity of a metabotropic glutamate receptor, such as mGluR5, by ametabotropic glutamate receptor ligand is provided. In one embodiment,the method comprises contacting mGluR5 receptor with a potentiator, anallosteric agonist, or a positive allosteric modulator of the mGluR5receptor in an amount effective to increase or augment the activity. Inanother embodiment, a potentiator, an allosteric agonist, or a positiveallosteric modulator of the mGluR5 receptor is a compound as disclosedherein.

In certain embodiments, a compound as disclosed herein inhibits orreduces the activity of metabotropic glutamate receptor, such as mGluR5.In some embodiments, the activity of mGluR5 is inhibited or reduced byabout 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 99% ormore, as compared with the activity obtained without contacting with thecompounds as disclosed herein. In certain embodiments, the inhibition orreduction of receptor activity is dose-dependent. Inhibition of mGluR5activity may be measured using assays known in the art, for example, thein vitro functional assays as described herein elsewhere. In oneembodiment, the functional assay utilizes an appropriate cell-lineexpressing the desired metabotropic glutamate receptor, such as mGluR5.In other embodiments, the functional assay utilizes synaptosomesisolated from brain tissue of an appropriate organism. In otherembodiments, inhibition of metabotropic glutamate receptor activity maybe assessed using receptor binding experiments known in the art, e.g.utilizing appropriate membrane preparations. In one embodiment, theassay involves treatment of a test subject (e.g., a mice or a rat) witha compound set forth herein as well as a reference compound, followed byisolation of brain tissue and ex vivo analysis of receptor occupancy. Inone embodiment, the mGluR5 modulator is a negative allosteric modulator.

In certain embodiments, methods of inhibiting or reducing the activityof a metabotropic glutamate receptor, such as mGluR5, in a subject(e.g., human) comprising administering to the subject an effectiveamount of a compound as disclosed herein are provided. In someembodiments, the activity of mGluR5 is inhibited or reduced by about 1%,about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about60%, about 70%, about 80%, about 90%, about 95%, about 99% or more, whenmeasured using an assay known in the art and compared to the activityobtained in the absence of administration of a compound as disclosedherein.

In one embodiment, a method of inhibiting or reducing the activity of ametabotropic glutamate receptor, such as mGluR5, by a metabotropicglutamate receptor ligand is provided. In one embodiment, the methodcomprises contacting mGluR5 receptor with an amount of an antagonist, aninverse agonist, or an allosteric modulator of the mGluR5 receptoreffective to inhibit or reduce the activity of the metabotropicglutamate receptor. In another embodiment, an antagonist, an inverseagonist, or an allosteric modulator of the mGluR5 receptor is a compoundas disclosed herein.

Treatment, Prevention, and/or Management of mGluR5 Related Disorders andConditions

In certain embodiments, a method of treating, preventing, and/ormanaging a neurological disorder, such as a neurodegenerative disorder,neuropsychiatric disorder, affective disorder, or a cognitive function,learning or memory disorder, comprising administering to a subject inneed thereof an effective amount of a compound as disclosed herein isprovided.

In certain embodiments, a method of treating psychosis, schizophrenia,cognitive impairment associated with schizophrenia, or a cognitivedisorder (such as Alzheimer's disease), comprising administering to asubject in need thereof an effective amount of a compound as disclosedherein is provided.

In certain embodiments, the compounds as disclosed herein inhibit theactivity of mGluR5. In certain embodiments, the compounds as disclosedherein are positive allosteric modulators of mGluR5. In otherembodiments, the compounds as disclosed herein are antagonists ofmGluR5. In certain embodiments, the compounds as disclosed herein areselective for mGluR5 over other CNS-related targets. In certainembodiments, the compounds as disclosed herein are highly brainpenetrable in mammals, such as rodents, and human. In some embodiments,inhibition or potentiation of mGluR5 activity may be assessed byfunctional assays as described herein elsewhere. In certain embodiments,the efficacious concentration of the compounds set forth herein is lessthan 10 nM, less than 100 nM, less than 1 μM, less than 10 μM, less than100 μM, less than 1 μM, or less than 1 mM. In other embodiments,compound's activity may be assessed in various art-recognized animalmodels.

In some embodiments, a method of treating, preventing, and/or managing aneurodegenerative disease [including but not limited to: Alzheimer'sdisease (including the accompanying symptoms of mild, moderate, orsevere cognitive impairment); amyotropic lateral sclerosis (ALS); anoxicand ischemic injuries; ataxia and convulsion (including for thetreatment and prevention of seizures that are caused by schizoaffectivedisorder or by drugs used to treat schizophrenia); benign forgetfulness;brain edema; cerebellar ataxia including McLeod neuroacanthocytosissyndrome (MLS); closed head injury; coma; contusive injuries (e.g.spinal cord injury and head injury); dementias including multi-infarctdementia and senile dementia; disturbances of consciousness; Downsyndrome; drug-induced or medication-induced Parkinsonism (such asneuroleptic-induced acute akathisia, acute dystonia, Parkinsonism, ortardive dyskinesia, neuroleptic malignant syndrome, ormedication-induced postural tremor); epilepsy; fragile X syndrome;Gilles de la Tourette's syndrome; head trauma; hearing impairment andloss; Huntington's disease; Lennox syndrome; levodopa-induceddyskinesia; mental retardation; movement disorders including akinesiasand akinetic (rigid) syndromes (including basal ganglia calcification,corticobasal degeneration, multiple system atrophy, parkinsonism-ALSdementia complex, Parkinson's disease, postencephalitic parkinsonism,and progressively supranuclear palsy); muscular spasms and disordersassociated with muscular spasticity or weakness including chorea (suchas benign hereditary chorea, drug-induced chorea, hemiballism,Huntington's disease, neuroacanthocytosis, Sydenham's chorea, andsymptomatic chorea), dyskinesia (including tics such as complex tics,simple tics, and symptomatic tics), myoclonus (including generalizedmyoclonus and focal cyloclonus), tremor (such as rest tremor, posturaltremor, and intention tremor), and dystonia (including axial dystonia,dystonic writer's cramp, hemiplegic dystonia, paroxymal dystonia, andfocal dystonia such as blepharospasm, oromandibular dystonia, andspasmodic dysphonia and torticollis); neuronal damage including oculardamage, retinopathy or macular degeneration of the eye; neurotoxicinjury which follows cerebral stroke, thromboembolic stroke, hemorrhagicstroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia,hypoxia, anoxia, perinatal asphyxia and cardiac arrest; Parkinson'sdisease; seizure; status epilecticus; stroke; tinnitus; tubularsclerosis; and viral infection induced neurodegeneration (including butlimited to neurodegeneration caused by caused by acquiredimmunodeficiency syndrome (AIDS) and encephalopathies)], comprisingadministering to a subject in need thereof an effective amount of acompound as disclosed herein is provided. For example, without beinglimited by a particular theory, mGluR5 modulators may be effective intreating Parkinson's disease, and efficacious in a variety of animalmodels for Parkinson's disease. See, e.g., Jaeschke, G., et al., ExpertOpin. Ther. Pat. 2008, 18, 123; Glatthar R., et al., WO 2006/89700 A1.

In some embodiments, a method of treating, preventing, and/or managing aneuropsychiatric disorder (including but limited to: aggression;attention disorders including attention-deficit disorder (ADD),attention-deficit-hyperactivity disorder (ADHD) and conduct disorder;delirium; delusional disorder; persisting dementia; pervasivedevelopment disorder including autism, autistic disorder and autismspectrum disorder, psychosis and psychotic disorders (includingpsychosis associated with affective disorders, brief reactive psychosis,brief psychotic disorder, shared psychotic disorder, psychotic disorderdue to a general medical condition and substance-induced or drug-inducedpsychotic disorder (e.g., caused by phencyclidine, ketamine and otherdissociative anaesthetics, amphetamine, cocaine and otherpsychostimulants)); schizophrenia (including schizoaffective psychosisand “schizophrenia-spectrum” disorders such as schizoid or schizotypalpersonality disorders, or illnesses associated with psychosis (such asmajor depression, manic depressive (bipolar) disorder, Alzheimer'sdisease and post-traumatic stress syndrome) including both the positiveand negative symptoms of schizophrenia and other psychoses); and sensoryhyper-excitability), comprising administering to a subject in needthereof an effective amount of a compound as disclosed herein isprovided.

In some embodiments, a method of treating, preventing and/or managingdisorders of cognition, learning or memory or of improving cognitivefunction, memory and learning abilities (including but not limited to:adult and childhood learning disorders; altruism; amnestic disorders(including Alzheimer's disease-related cognitive decline, normalage-related cognitive decline and persisting amnestic disorder);associative learning; attention; benign forgetfulness; cognitivedeficits induced by situational stress (including but not limited tooperating machinery for extended time periods or working in emergency orcombat situations); cognitive disorders including dementia (associatedwith acquired immunodeficiency disease, Alzheimer's disease,Creutzfeldt-Jacob disease, HIV infection, Huntington's disease,ischemia, multi-infarct dementia, Parkinson's disease, perinatalhypoxia, Pick's disease, trauma, vascular problems or stroke, othergeneral medical conditions or substance abuse); cooperativity;declarative memory; early consolidation; empathy; episodic memory;executive function; explicit memory; implicit memory; imprinting;language; late consolidation; learning (including electronic, formal,informal, multimedia and rote learning); low IQ; memory deficit; memoryloss; mild cognitive impairment (MCI); non-verbal and verbalcommunicative skills; play; rehearsal; retrieval, semantic memory;sensory integration of environmental cues including temperature, odor,sounds, touch, and taste; social cognition; and speech disorders),comprising administering to a subject in need thereof an effectiveamount of a compound as disclosed herein is provided.

In some embodiments, a method of treating, preventing, and/or managinggastrointestinal disorders (including but not limited to acid reflux;dyspepsia; gastroesophageal reflux disorder (GERD); and irritable bowelsyndrome), comprising administering to a subject in need thereof aneffective amount of a as disclosed herein is provided. For example,without being limited by a particular theory, mGluR5 modulators may beeffective in treating gastrointestinal disorders in human. See, e.g.,Jaeschke, G., et al., Expert Opin. Ther. Pat. 2008, 18, 123; Bolea C.,et al., WO 2004/78728 A1.

In some embodiments, a method of treating, preventing, and/or managingall categories of pain (including but not limited to: pain described interms of stimulus or nerve response; somatic pain (normal nerve responseto a noxious stimulus); neuropathic pain (abnormal response of a injuredor altered sensory pathway often without clear noxious input, andincluding chemotherapy-induced neuropathy, diabetic peripheralneuropathic pain, HIV/AIDS peripheral neuropathy, neuropathic cancerpain, and post-herpetic neuralgia); abdominal pain; acute thermalhyperalgesia; allodynia; burns; causalgia; central pain; complexregional pain syndrome (CRPS); dental pain; dual mechanism pain;dysesthesia; ear ache; episiotomy pain; eye pain; fibromyalgia;gynecological pain including dysmeorrhoea; headache (including acute andchronic tension headache and cluster headache); heart pain;hyperalgesia; hyperesthesia; hyperpathia; itching conditions includingcontact dermatitis, pruritis, and itch due to atopic dermatitis andhemodialysis; labor pain; low back pain; mechanical allodynia; mixedetiology pain; musculo-skeletal pain including that following physicaltrauma; neck pain; orofacial pain; pain associated with cystitis; paincause by convulsion; pain resulting from dysfunction of the nervoussystem (i.e., organic pain states that share clinical features ofneuropathic pain and possibly common pathophysiology mechanism, but arenot initiated by an identifiable lesion in any part of the nervoussystem); pain that is a symptom or a result of a disease state orsyndrome (such as AIDS pain, ankylosing spondylitis; arthritis pain,cancer pain, cardiac ischaemia, carpal tunnel syndrome, diabeticperipheral neuropathic pain, episcleritis, gout, inflammation, irritablebowel syndrome, migraine, neuropathy arising from chronic alcohol use,repetitive motion injury, pain from autoimmune diseases, pain fromrespiratory diseases, scar pain, sciatica; scleritis; and trigeminalneuralgia); pain that is categorized in terms of its severity (mild,moderate, or severe pain); pain that is categorized temporally (chronicpain and acute pain); phantom limb pain; post-surgical pain; reflexsympathetic dystrophy; sinus pain; and visceral pain) comprisingadministering to a subject in need thereof an effective amount of acompound as disclosed herein is provided. See e.g., Jaeschke, G., etal., Expert Opin. Ther. Pat. 2008, 18, 123; Cosford, N. D. P., et al.,WO 2003/51315 A2.

In some embodiments, a method of treating, preventing, and/or managingmigraine, comprising administering to a subject in need thereof aneffective amount of a compound as disclosed herein is provided. Forexample, without being limited by a particular theory, mGluR5 modulatorsmay be effective in the treatment and prevention of migraine in human,and may have comparable efficacy to triptans in treating migraine. See,e.g., Jaeschke, G., et al., Expert Opin. Ther. Pat. 2008, 18, 123.

In some embodiments, a method of treating, preventing, and/or managingsubstance abuse disorder or eating disorder (including but not limitedto the abuse of or addiction to cannabis, cocaine, morphine, opioid,nicotine, or alcohol; substance-abuse related disorders and addictivebehaviors (including substance-induced delirium); tolerance, dependenceor withdrawal from substances including alcohol, amphetamines,anxiolytics, cannabis, cocaine, hallucinogens, hypnotics, inhalants,nicotine, opioids, phencyclidine, or sedatives; anorexia nervosa; bingeeating; bulimia nervosa; cachexia; compulsive eating disorder, emesis;and obesity) comprising administering to a subject in need thereof aneffective amount of a compound as disclosed herein is provided. Seee.g., Jaeschke, G., et al., Expert Opin. Ther. Pat. 2008, 18, 123.

In other embodiments, a method of treating, preventing, and/or managinga disorder of the genitourinary tract or a sexual disorder (includingbut limited to: lower urinary tract disorder; overactive bladder,urinary incontinence including without limitation involuntary voiding ofurine, dribbling or leakage of urine, stress urinary incontinence (SUI),urge incontinence, urinary exertional incontinence, reflex incontinence,passive incontinence, and overflow incontinence; and sexual dysfunction,in men or women, including without limitation sexual dysfunction causedby psychological and/or physiological factors, erectile dysfunction,premature ejaculation, vaginal dryness, lack of sexual excitement,inability to obtain orgasm, and psychosexual dysfunction, includingwithout limitation, inhibited sexual desire, inhibited sexualexcitement, inhibited female orgasm, inhibited male orgasm, functionaldyspareunia, functional vaginismus, and atypical psychosexualdysfunction), comprising administering to a subject in need thereof aneffective amount of a compound as disclosed herein is provided.

In other embodiments, a method of treating, preventing, and/or managingcancer, including but not limited to, oral cancer and glioneuronalcancer, comprising administering to a subject in need thereof aneffective amount of a compound as disclosed herein is provided.

In some embodiments, a compound as disclosed herein is active in atleast one model, which can be used to measure the activity of thecompounds and estimate their efficacy in treating a disorder related tomGluR5. For example, when the model is for depression (e.g., meanimmobility), the compounds are active when they inhibit mean immobilityof a test subject by about 5%, about 10%, about 20%, about 30%, about40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%,about 99%, or more, when compared to vehicle. In some embodiments, thecompound as disclosed herein produce a similar disparity in measuredendpoint between treated animals and animals administered vehicle.

Other exemplary diseases and conditions that may be treated, prevented,and/or managed using the methods, compounds as disclosed herein andcompositions thereof, include, but are not limited to: metabolicdiseases including diabetes and pulmonary/respiratory diseases includingasthma, chronic obstructive pulmonary disease (COPD), chronicbronchitis, cystic fibrosis, and emphysema.

In certain embodiments, the compounds as described herein treat,prevent, and/or manage a neurological disorder, without causingaddiction to said compounds. Any suitable route of administration can beemployed for providing the patient with a therapeutically orprophylactically effective dose of an active ingredient. For example,oral, mucosal (e.g., nasal, sublingual, buccal, rectal, vaginal),parenteral (e.g., intravenous, intramuscular), transdermal, andsubcutaneous routes can be employed. Exemplary routes of administrationinclude oral, transdermal, and mucosal. Suitable dosage forms for suchroutes include, but are not limited to, transdermal patches, ophthalmicsolutions, sprays, and aerosols. Transdermal compositions can also takethe form of creams, lotions, and/or emulsions, which can be included inan appropriate adhesive for application to the skin or can be includedin a transdermal patch of the matrix or reservoir type as areconventional in the art for this purpose. An exemplary transdermaldosage form is a “reservoir type” or “matrix type” patch, which isapplied to the skin and worn for a specific period of time to permit thepenetration of a desired amount of active ingredient. The patch can bereplaced with a fresh patch when necessary to provide constantadministration of the active ingredient to the patient.

The amount to be administered to a patient to treat, prevent, and/ormanage the disorders described herein will depend upon a variety offactors including the activity of the particular compound employed, orthe ester, salt or amide thereof, the route of administration, the timeof administration, the rate of excretion or metabolism of the particularcompound being employed, the duration of the treatment, other drugs,compounds and/or materials used in combination with the particularcompound employed, the age, sex, weight, condition, general health andprior medical history of the patient being treated, and like factorswell known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount required. For example, thephysician or veterinarian could start doses of the compounds employed atlevels lower than that required in order to achieve the desiredtherapeutic effect and gradually increase the dosage until the desiredeffect is achieved.

In general, a suitable daily dose of a compound set forth herein will bethat amount of the compound which is the lowest dose effective toproduce a therapeutic or prophylactic effect. Such an effective dosewill generally depend upon the factors described above. Generally, oral,intravenous, intracerebroventricular, and subcutaneous doses of thecompounds set forth herein for a patient will range from about 0.005 toabout 100 mg per kilogram or about 0.05 mg per kilogram to about 5 mgper kilogram of body weight per day. In one embodiment, the oral dose ofa compound set forth herein will range from about 1 mg to about 1 g perday or 10 mg to about 300 mg per day. In another embodiment, the oraldose of a compound set forth herein will range from about 20 mg to about250 mg per day. In another embodiment, the oral dose of a compound setforth herein will range from about 100 mg to about 300 mg per day. Inanother embodiment, the oral dose of a compound set forth herein willrange from about 10 mg to about 100 mg per day. In another embodiment,the oral dose of a compound set forth herein will range from about 25 mgto about 50 mg per day. In another embodiment, the oral dose of acompound set forth herein will range from about 50 mg to about 200 mgper day. Each of the above-recited dosage ranges may be formulated as asingle or multiple unit dosage formulations.

In some embodiments, the compounds disclosed herein may be used incombination with one or more second active agents to treat, prevent,and/or manage disorders described herein. In certain embodiments, thesecond compound is an antipsychotic agent. In certain embodiments, thesecond active agent is an atypical antipsychotic agent. In certainembodiments, the second active agent is an agent that is useful for thetreatment of Alzheimer's disease. In certain embodiments, the secondactive agent is a cholinesterase inhibitor. In certain embodiments, thesecond active agent is lurasidone, olanzapine, risperidone,aripiprazole, amisulpride, asenapine, blonanserin, clozapine,clotiapine, illoperidone, mosapramine, paliperidone, quetiapine,remoxipride, sertindole, sulpiride, ziprasidone, zotepine, pimavanserin,loxapine, donepezil, rivastigmine, memantine, galantamine, tacrine,amphetamine, methylphenidate, atomoxetine, modafinil, sertraline,fluoxetine, or L-DOPA.

EXAMPLES

Certain embodiments are illustrated by the following non-limitingexamples.

Synthesis of Compounds

In the examples below, unless otherwise indicated, all temperatures areset forth in degrees Celsius and all parts and percentages are byweight. Reagents may be purchased from commercial suppliers, such asSigma-Aldrich Chemical Company, and may be used without furtherpurification unless otherwise indicated. Reagents may also be preparedfollowing standard literature procedures known to those skilled in theart. Solvents may be purchased from Aldrich in Sure-Seal bottles andused as received. All solvents may be purified using standard methodsknown to those skilled in the art, unless otherwise indicated.

The reactions set forth below were done generally at ambienttemperature, unless otherwise indicated. The reaction flasks were fittedwith rubber septa for introduction of substrates and reagents viasyringe. Analytical thin layer chromatography (TLC) was performed usingglass-backed silica gel pre-coated plates (Merck Art 5719) and elutedwith appropriate solvent ratios (v/v). Reactions were assayed by TLC orLCMS, and terminated as judged by the consumption of starting material.Visualization of the TLC plates was done with UV light (254 wavelength)or with an appropriate TLC visualizing solvent, such as basic aqueousKMnO₄ solution activated with heat. Flash column chromatography (See,e.g., Still et al., J. Org. Chem., 43: 2923 (1978)) was performed usingsilica gel 60 (Merck Art 9385) or various HPLC systems.

The compound structures in the examples below were confirmed by one ormore of the following methods: proton magnetic resonance spectroscopy,mass spectroscopy, and melting point. Proton magnetic resonance (¹H NMR)spectra were determined using an NMR spectrometer operating at 400 MHzfield strength. Chemical shifts are reported in the form of delta (6)values given in parts per million (ppm) relative to an internalstandard, such as tetramethylsilane (TMS). Alternatively, ¹H NMR spectrawere referenced to signals from residual protons in deuterated solventsas follows: CDCl₃=7.25 ppm; DMSO-d⁶=2.49 ppm; C₆D₆=7.16 ppm; CD₃OD=3.30ppm. Peak multiplicities are designated as follows: s, singlet; d,doublet; dd, doublet of doublets; t, triplet; dt, doublet of triplets;q, quartet; br, broadened; and m, multiplet. Coupling constants aregiven in Hertz (Hz). Mass spectra (MS) data were obtained using a massspectrometer with APCI or ESI ionization.

As used herein, and unless otherwise specified, “4 Å MS” means 4angstrom molecular sieves, “Ac” means acetyl, “AIBN” means2,2′-azobisisobutyronitrile, “aq” means aqueous, “BINAP” means2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, “Bn” means benzyl, “BOC” or“Boc” means t-butyloxycarbonyl, “cat.” means catalytic, “Cbz” or “Z”means benzyloxycarbonyl, “CDI” means carbonyldiimidazole, “DAST” means(diethylamino)sulfur trifluoride (Et₂NSF₃), “DBU” means1,8-diazabicyclo[5.4.0]undec-7-ene, “DCE” means 1,2-dichloroethane,“DCM” means dichloromethane, “DDQ” means2,3-dichloro-5,6-dicyano-1,4-benzoquinone, “Dess-Martin reagent” means1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (alsocalled DMP), “DIEA” or “DIPEA” means diisopropylethylamine, “DMAP” means4-dimethylaminopyridine, “DME” means 1,2-dimethoxyethane, “DMF” meansdimethylformamide, “DMF-DMA” means N,N-dimethylformamide dimethylacetal,“DMSO” means dimethyl sulfoxide, “dppf” means1,1′-bis(diphenylphosphino)ferrocene, “EDCI” meansN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, “ee” meansenantiomeric excess, “equiv” and “eq” mean equivalent(s), “it” meansethyl, “EtOAc” means ethyl acetate, “EtOH” means ethanol, “Fmoc” means9-fluorenylmethoxycarbonyl, “h” or “hr” means hour(s), “HOBt” meanshydroxybenzotriazole, “HPLC” means High Pressure Liquid Chromatography”,“LAH” means lithium aluminum hydride, “LDA” means lithiumdiisopropylamide, “M” means molar concentration, “m-CPBA” means3-chloro-pertenzoic acid, “Me” means methyl, “MeCN” means acetonitrile,“MeOH” means methanol, “Ms” means mesyl (CH₃SO₂—), “min” meansminute(s), “MTBE” means methyl t-butyl ether, “NBS” meansN-bromosuccinimide, “NFSI” means N-Fluorobenzenesulfonimide, “NMP” meansN-methylpyrrolidone, “PCC” means pyridinium chlorochromate, “PE” meanspetroleum ether, “PPA” means polyphosphoric acid, “psi” or “PSI” meanspounds force per square inch, “RT” or “rt” means room temperature, “Rt”means retention time, “Selectfluor” means1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.0]octaneditetrafluoroborate, “t” means tert, “TBDMSCl” meanstert-butyldimethylsilyl chloride, “t-BuOH” means tert-butanol, “t-BuONa”means sodium tert-butoxide, “TBTU” means2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate,“TEA” means triethylamine, “Tebbe Reagent” meansμ-chloro[di(cyclopenta-2,4-dien-1-yl)]dimethyl(μ-methylene)titaniumaluninum,“Tf” means trifluoromethanesulfonyl, “TFA” means trifluoroacetic acid,“THF” means tetrahydrofuran, “TosMIC” meansp-toluenesulfonylmethylisocyanide, “TMSI” means iodotrimethylsilane,“o-Tol” means o-tolyl (2-CH₃C₆H₄), “m-Tol” means m-tolyl (4-CH₃C₄H₄),“Ts” means tosyl (p-CH₃C₆H₄SO₂), and “Xantphos” means4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

For those compounds containing basic nitrogen center(s), its HCl saltwas prepared by treating the freebase with excess HCl etherate solution.

General Synthesis Experimentals General Example A: Coupling ChemistryExample A1. General Experimental for Coupling of an Aromatic Bromide orAromatic Chloride with an Aromatic Alkyne

To a solution of6-bromo-2-ethyl-2-methyl-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one(1 equiv) in DMF (0.05 M) was charged 2-ethynylpyridine (approx. 2.5equiv), Pd(OAc)₂ (0.2 equiv), PPh₃ (0.9 equiv), CuI (0.2 equiv) and Et₃N(0.2 equiv). A vacuum was applied and the reaction mixture was backfilled with nitrogen three times. The mixture was stirred atapproximately 70° C. until the reaction was complete. The reaction wasthen cooled to room temperature, diluted with H₂O, and extracted withethyl acetate. The combined organic layers were washed with brine anddried over anhydrous sodium sulfate, then concentrated under reducedpressure and purified by column chromatography to give the desiredproduct.

Example A2. General Experimental for Coupling of an Aromatic Bromide orAromatic Chloride with an Aromatic Alkyne

Example A2, Step 1

To a solution of the aromatic bromide (e.g.,3-bromo-7,7-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one,1 equiv) in DMF (0.14 M) was charged ethynyltrimethylsilane (2 equiv),Pd(AcO)₂ (0.2 equiv), PPh₃ (0.8 equiv), CuI (0.2 equiv) and Et₃N (0.2equiv). The mixture was stirred in a sealed tube at approximately 80° C.until the reaction was complete (approximately 3.5 h). The reaction wasthen cooled to room temperature, diluted with H₂O, and extracted withethyl acetate. The combined organic layers were washed with brine anddried over anhydrous sodium sulfate, then concentrated under reducedpressure to obtain the desired trimethylsilylalkyne-containing desiredproduct (e.g.,7,7-dimethyl-3-((trimethylsilyl)ethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one).The crude product was directly used for the next step withoutpurification.

Example A2, Step 2

A solution of the trimethylsilylalkyne-containing starting material(e.g.,7,7-dimethyl-3-((trimethylsilyl)ethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one, 1 equiv) and 1 N KOH aqueous in methanol wasstirred at mom temperature until the reaction was complete(approximately 0.5 h). The reaction mixture was quenched with water andextracted with ethyl acetate. The combined organic layers were washedwith brine and dried over anhydrous sodium sulfate, then concentratedunder reduced pressure. The desired deprotected alkyne (e.g.,3-ethynyl-7,7-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one) was obtained by silica gel chromatographypurification.

Example A3. General Experimental for the Suzuki Coupling of ArylBromides or Chlorides with Boronic Acids

A solution of the aryl bromide or aryl chloride (e.g.,6-bromonicotinonitrile, 1 equiv),4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (2 equiv), K₂CO₃ (2equiv), Pd(AcO)₂ (0.4 equiv) and Ph₃P (0.8 equiv) in 1,4-dioxane wasstirred under N₂ at 85° C. until the reaction was complete(approximately 4 h). After cooling to room temperature, the mixture wasquenched with water (50 mL) and extracted with ethyl acetate (3×50 mL).The combined organic layers were dried over Na₂SO₄ and concentratedunder reduced pressure. The crude vinyl-containing product (e.g.,2-vinylisonicotinonitrile) was purified by silica gel chromatography.

Example A4. General Experimental for the Suzuki Coupling of ArylBromides or Chlorides with Aryl Bromides, Chlorides or Iodines

Example A4, Step 1

A solution of aryl bromide (e.g.,3-bromo-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one,1 equiv), bis(pinacolato)diboron (1.2 equiv), CH₃COOK (2 equiv) andtetrakis(triphenylphosphine)palladium (0.05 equiv) in 1,4-dioxane wasstirred under N₂ at 90° C. for 6 h After cooling to room temperature,the reaction mixture was poured into H₂O and extracted with EtOAc. Thecombined organic layers were washed with brine, then dried over Na₂SO₄.After filtration and concentration, the crude product was purified bycolumn chromatography (EtOAc:n-hexane=1:5) to give the desired boricester (e.g.,8,8-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one).

Example A4, Step 2

A solution of the boric ester (e.g.,8,8-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one,1 equiv), aryl bromide (e.g., 2-bromobenzo[d]thiazole, 1.5 equiv),Cs₂CO₃ (2 equiv), tetrakis(triphenylphosphine)palladium (0.1 equiv) inDMF was warmed to 160° C. by microwave reaction for 10 min. Aftercooling to room temperature, the reaction mixture was diluted H₂O andextracted with EtOAc. The combined organic layers were washed withbrine, dried over Na₂SO₄. After filtration and concentration, theresidue was purified by preparative chromatography to give the C—Ccoupling product (e.g.,3-(benzo[d]thiazol-2-yl)-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one).

Example A5. General Experimental for the Still Coupling of Aryl Bromidesor Aryl Chlorides with Tin

A solution of aryl bromide or aryl chloride (e.g.,[2,1-b]quinazolin-11(7H)-one, 1 equiv), 2-(tributylstannyl)pyridine (1.5equiv), tetrakis(triphenylphosphine)palladium (0.1 equiv) and CsF (2.2equiv) in DMF was warmed to 90° C. for 20 min by microwave reactor. Thereaction mixture was poured into H₂O and extracted with EtOAc. Thecombined organic layers were washed with brine and dried over Na₂SO₄.After filtration and concentration, the residue was washed with ethylether to give the desired C—C coupling product (e.g.,8,8-dimethyl-3-(2-(pyridin-2-yl)pyrimidin-5-yl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one).

Example A6. General Experimental for the Negishi Cross-Coupling

To a solution of tetrakis(triphenylphosphine)palladium (0.05 equiv) inTHF was added the organozinc reagent (e.g., pyridin-2-ylzinc bromide, 2equiv) at 15° C. under N₂. Then, a solution of aryl iodine (e.g.,2-chloro-5-iodopyrimidine, 1 equiv) in THF was added. The reactionmixture was stirred at room temperature for 3 h. The mixture was pouredinto H₂O and extracted with EtOAc. The combined organic layers werewashed with brine, dried over Na₂SO₄. After filtration andconcentration, the crude product was purified by silica-gel column togive the C—C coupling product (e.g.,2-chloro-5-(pyridin-2-yl)pyrimidine).

Example A7. General Experimental for the Coupling of Thiazole-H withAryl Iodine

A solution of thiazole (e.g.,8,8-dimethyl-3-(thiazol-2-yl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one,1 equiv), aryl iodine (e.g., 2-iodopyridine, 1.3 equiv),Pd(dppf)Cl₂.CH₂Cl₂ (0.15 equiv), Ag₂CO₃ (2 equiv) and PPh₃ (1 equiv) inH₂O was stirred at 60° C. under N₂ overnight. Then, CH₂Cl₂ was added todilute the mixture. After filtration, the reaction mixture was extractedwith CH₂Cl₂. The combined organic layers were washed with brine, driedover Na₂SO₄. After filtration and concentration, the crude product waspurified by preparative chromatography to give the desired product.

Example A8. General Experimental for the Coupling ofBis(Pinacolato)Diboron with Triflate

Example A8, Step 1

To a solution of diisopropylamine (1.2 equiv) in dry THF was addedn-BuLi (1.2 equiv) slowly at 0° C. under nitrogen. After 30 min, themixture was cooled to −78° C., and then the ketone (e.g., tert-butyl3-oxopyrrolidine-1-carboxylate, 1 equiv) in THF was added dropwise. Themixture was stirred for 30 min. Tf₂NPh (1.1 equiv) in THF was addeddropwise to the reaction mixture and stirred at 0° C. overnight. Themixture was concentrated and purified column chromatography through aplug of alumina (ethyl acetate:heptane=1:9) to give the triflate (e.g.,tert-butyl4-(trifluoromethylsulfonyloxy)-2,3-dihydro-1H-pyrrol-1-carboxylate).

Example A8, Step 2

To a stirred solution of the triflate (e.g., tert-butyl4-(trifluoromethylsulfonyloxy)-2,3-dihydro-1H-pyrrole-1-carboxylate, 1equiv), Pd(dppf)Cl₂ (0.02 equiv), bis(pinacolato)diboron (1 equiv) andpotassium carbonate (2 equiv) in 1,4-dioxane was heated at 80° C.overnight. After cooling to room temperature, the mixture was dilutedwith water and extracted with ethyl acetate. The combined organic phasewas washed with brine, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The residue was purified by columnchromatography on silica gel to give the boric ester (e.g., tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-pyrrole-1-carboxylate).

General Example B: Condensation Chemistry Example B1. GeneralExperimental for the Condensation of a Lactam with an Aromatic AminoAcid

To a solution of an aromatic amino acid (e.g., 2-amino-4-bromobenzoicacid, 1.1 equiv) and a lactam (e.g., 4-ethyl-4-methylpyrrolidin-2-one, 1equiv) in toluene (0.15 M) was charged POCl₃ (1.2 equiv) and the mixturewas stirred at 80° C. until the reaction was complete (approximately 5h), then the reaction was cooled to room temperature, and an Na₂CO₃aqueous solution was added. The water layer was extracted with ethylacetate and the combined organic layers were dried over Na₂SO₄,filtered, and evaporated to give the desired product (e.g.,6-bromo-2-ethyl-2-methyl-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one),which was used directly for the next step.

Example B2. General Experimental for the Condensation of an Imidate witha Bromoisochroman-1,3-Dione or a Chloroisochroman-1,3-Dione

A mixture of the 6-bromoisochroman-1,3-dione and the imidate (e.g.,7-methoxy-4-methyl-3,4,5,6-tetrahydro-2H-azepine, 1 equiv) in toluene(approximately 0.06 M) was refluxed until the reaction was complete. Thecrude product was concentrated under reduced pressure and then purifiedby silica gel chromatography to give the desired bromoisoquinolinoneproduct.

Example B3. General Experimental for the Synthesis of Precursors,Condensation to Quinazoline-2,4(1H,3H)-Diones, and Further RingCyclization

Example B3, Step 1

The solution of the amino-ester starting material (e.g., ethyl2-amino-4-bromobenzoate, 1 equiv), ethyl chloroformate (2 equiv), K₂CO₃(2 equiv) in 1,4-dioxane (0.24 M) was stirred at approximately 70° C.until the reaction was complete. The reaction was diluted with H₂O (200mL) and extracted with EtOAc. The organic layers were washed with brine,dried over NaSO₄ and concentrated to give the desired carbonate product(e.g. ethyl 4-bromo-2-(ethoxycarbonylamino)benzoate).

Example B3, Step 2

A mixture of the carbonate starting material (e.g., ethyl4-bromo-2-(ethoxycarbonylamino)benzoate, 1 equiv) and neat amino alcohol(e.g., 3-amino-2,2-dimethylpropan-1-ol, 20 equiv) was stirred atapproximately 120° C. overnight. The reaction mixture was concentratedand the residue was purified by column chromatography to give thedesired alcohol-containing product (e.g.,7-bromo-3-(3-hydroxy-2,2-dimethylpropyl)quinazoline-2,4(1H,3H)-dione).

Example B3, Step 3

To a solution of the alcohol-containing starting material (e.g.,7-bromo-3-(3-hydroxy-2,2-dimethylpropyl)quinazolin-2,4(1H,3H)-dione, 1equiv) in CH₂Cl₂(0.03 M) was added methanesulfonyl chloride (2 equiv)and Et₃N (2.5 equiv). The mixture was stirred at room temperatureovernight or until complete. The reaction mixture was concentrated andthe residue was purified by column chromatography to give the desiredproduct (e.g.,9-bromo-3,3-dimethyl-3,4-dihydro-[1,3]oxazino[2,3-b]quinazolin-6(2H)-one).

Example B4. General Experimental for the Synthesis of Precursors,Condensation to Bromoisochroman-1-Diones

Example B4, Step 1

To a stirred mixture of iron powder (10 g, 178.6 mmol) and ammoniumchloride (2.4 g, 44.8 mmol) in H₂O (200 mL) was added diethyl4-nitrophthalate (8 g, 28.4 mmol) at 55° C. After stirring at the sametemperature for 3 hours, the reaction mixture was basified to pH to 9with aqueous solution of sodium hydroxide and extracted with ethylacetate (2×200 mL). The combined organic layers were washed with brine(200 mL), dried over Na₂SO₄ and concentrated under reduced pressure. Thecrude product (diethyl 4-aminophthalate) was used for the next stepwithout further purification. MS (ESI+): m/z 238 (MH⁺).

Example B4, Step 2

To a solution of diethyl 4-aminophthalate (7.0 g, 27.9 mmol) in 250 mLacetonitrile below 0° C. was added cuprous bromide (9.2 g, 55.8 mmol)and then t-butyl nitrite. The mixture was warmed to room temperature andstirred overnight. The reaction mixture was then concentrated to 100 mLand diluted with water (300 mL). The resulting mixture was adjusted topH around 5-6 and extracted with ethyl acetate (3×300 mL). The combinedorganic layers were washed with brine and dried over Na₂SO₄. Afterfiltration and concentration, the residue was purified by silica gelchromatography to give 5.0 g of diethyl 4-bromophthalate. MS (ESI+): m/z301, 303 (MH⁺).

Example B4, Step 3

To a solution of diethyl 4-bromophthalate (5.0 g, 15.9 mmol) inacetonitrile (180 mL) was added an aqueous solution (60 mL) of potassiumhydroxide (3.6 g, 63.7 mmol). The mixture was stirred at 60° C.overnight and then concentrated to 100 mL. The residue was diluted with150 mL of water, adjusted pH to 2 and extracted with ethyl acetate(3×300 mL). The combined organic layers were washed with brine, driedover Na₂SO₄ and concentrated under reduced pressure to give4-bromo-2-carboxymethyl-benzoic acid (4.5 g).

Example B4, Step 4

A solution of 4-bromo-2-carboxymethyl-benzoic acid (500 mg, 1.94 mmol)in 4 mL acetone was treated with acetyl chloride (912 mg, 11.6 mmol) andthe solution was stirred at room temperature for 17 h. The reactionmixture was concentrated and then azeotroped with toluene to yield thecrude desired product and it was used for the next step without furtherpurification.

Example B5. General Experimental for the Condensation of a Lactam withan Aromatic Amino Acid

Example B5, Step 1

A solution of the lactam (e.g., 2-oxa-6-azaspiro[3.4]octan-7-one, 1equiv) and methyl trifluoromethanesulfonate (2 equiv) in CH₂Cl₂ (0.03 M)was stirred at room temperature until the reaction was complete(approximately 5 h). The reaction mixture was then quenched withsaturated sodium carbonate and extracted with CH₂Cl₂. The combinedorganic layers were washed with brine, dried over Na₂SO₄ andconcentrated to give the desired product (e.g.,7-methoxy-2-oxa-6-azaspiro[3.4]oct-6-ene).

Example B5, Step 2

A solution of the starting material (e.g.,7-methoxy-2-oxa-6-azaspiro[3.4]oct-6-ene, 1 equiv) and3-amino-5-bromopicolinic acid (1.5 equiv) in toluene (0.02 M) wasrefluxed under nitrogen atmosphere until the reaction was complete.After concentration, the residue was purified by silica gelchromatography to give the desired product (e.g.,6′-bromo-1′H-spiro[oxetane-3,2′-pyrrolo[2,1-b]quinazolin]-9′(3′H)-one).

General Example C: Synthesis of Lactam and Isoxazolidin-3-One StartingMaterials Example C1. General Experimental for the Synthesis of LactamStarting Materials

Example C1, Step 1, Version 1

To a 1 M suspension of 60% NaH (approximately 1.25 equiv) in anhydrousTHF was added triethyl phosphonoacetate (approximately 1.25 equiv) atapproximately 0° C. under nitrogen atmosphere. The mixture was stirredat room temperature for 1 h, then the ketone (e.g., butan-2-one, 1equiv) was added and the mixture was refluxed until the reaction wascomplete (approximately 1 h). The mixture was poured in water andextracted with Et₂O. The organic layers were washed with brine anddried. The solvent was evaporated to give the desired productα,β-unsaturated ester (e.g., ethyl 3-methylpent-2-enoate).

Example C1, Step 1, Version 2

To the 0.4 M solution of carboethoxymethylidene triphenyl phosphorane(approximately 1.2 equiv) in dry THF was added the ketone startingmaterial (e.g., trifluoroacetaldehyde hydrate, 1 equiv). The reactionwas stirred at room temperature until the reaction was complete. Thesolvent was evaporated, and ethyl ether was added. The mixture wasfiltered and the residue was washed with ethyl ether. The filtrate wasdried over Na₂SO₄ and concentrated under reduced pressure. The desiredproduct α,β-unsaturated ester (e.g., ethyl 4,4,4-trifluorobut-2-enoate)used for the next reaction without further purification.

Example C1, Step 2

To a mixture of α,β-unsaturated ester (e.g., ethyl3-methyl-pent-2-enoate, 1 equiv) and the nitroalkane (e.g., MeNO₂,approximately 5.2 equiv) was slowly added DBU (approximately 1 equiv) atapproximately 0° C. under nitrogen atmosphere, then the mixture wasstirred at 25° C. until the reaction was complete (approximately 3 h).The reaction was quenched with 6 M HCl, and extracted with Et₂O. Theorganic layers were washed with brine and dried over Na₂SO₄. Afterconcentration, the residue was purified by silica gel chromatography togive the desired nitro-containing product (e.g., ethyl3-methyl-3-(nitromethyl)pentanoate).

Example C1, Step 3

The solution of the nitro-containing starting material (e.g., ethyl3-methyl-3-(nitromethyl)pentanoate, 1 equiv), 10% Pd/C (approximately14.5 mg/mmol nitro-containing starting material) in methanol(approximately 0.14 M) was stirred under a hydrogen atmosphere until thehydrogenation of the nitro group was complete. The mixture was filteredand the solvent was evaporated under reduced pressure. The residue wasdissolved in ethanol and refluxed until the cyclization was complete(approximately 2 h). The solvent was concentrated to give the desiredlactam product (e.g., 4-ethyl-4-methylpyrrolidin-2-one).

Example C2. General Experimental for the Synthesis of Lactam StartingMaterials

Example C2, Step 1

A solution of the ketone starting material (e.g.,3-methylcyclopentanone, 1 equiv), hydroxylamine hydrochloride (2.0equiv) and Na₂CO₃ (3 equiv) in MeOH/water (1.7:1, 0.6 M) was stirred atroom temperature until the reaction was complete (approximately 5 h).The solvent was then removed from the reaction mixture under reducedpressure. The residue was partitioned between ethyl acetate and water,and the organic layer was washed with brine and dried over anhydroussodium sulfate. Concentration under reduced pressure provided the crudeproduct (e.g., 3-methylcyclopentanone oxime) that was used withoutpurification in the next step.

Example C2, Step 2

To a solution of the oxime starting material (e.g.,3-methylcyclopentanone oxime, 1 equiv) and Na₂CO₃ (4 equiv) in acetone(0.18 M) and water (0.18 M) was added phenylsulfonyl chloride (2 equiv)dropwise at 0° C. The reaction mixture was stirred overnight, quenchedwith water, and extracted with CH₂Cl₂. The combined organic layers weredried over Na₂SO₄ and concentrated under reduced pressure to give thedesired lactam product (e.g. 4-methylpiperidin-2-one and5-methylpiperidin-2-one).

Example C3. General Experimental for the Synthesis of Isoxazolidin-3-OneStarting Materials

Sodium (0.45 g, 19.57 mmol) was dissolved in methanol (30 mL) at roomtemperature, and then hydroxy urea (1 equiv) was added slowly.α,β-Unsaturated ester (e.g., 3-methyl-but-2-enoic acid ethyl ester, 1equiv) was added dropwise. The reaction mixture was stirred at roomtemperature until the reaction was complete (approximately 18 hours).The solid was removed by filtration and the filtrate was concentrated.The residue was dissolved in water and stirred for approximately 15minutes, and then aqueous hydrochloric acid (2 M) was added dropwise toacidify the mixture. The aqueous solution was extracted with CH₂Cl₂. Theorganic layers were washed with brine, dried over magnesium sulfate andconcentrated to give the desired isoxazolidin-3-one (e.g.,5,5-dimethyl-isoxazolidin-3-one).

Example C4. General Experimental for the Synthesis of Lactam StartingMaterials

To a solution of the amine starting material (e.g. tert-butyl4-fluoro-4-methylazepane-1-carboxylate, 1 equiv) in ethyl acetate (0.07M) and water (0.1 M) was added RuO₂ (0.4 equiv) and NaIO₄ (5 equiv). Themixture was stirred at room temperature for 1 hour, then the solutionwas heated at 70° C. until the reaction was complete (approximately 3h). The reaction was then cooled to room temperature, and the mixturewas diluted with water and extracted with ethyl acetate. The combinedorganic phase was washed with Na₂CO₃ solution, dried over anhydrousNa₂SO₄ and concentrated under reduce pressure. The crude was purified bysilica gel chromatography to give the desired amide-containing product(e.g., tert-butyl 5-fluoro-5-methyl-2-oxoazepane-1-carboxylate).

Example C5. General Experimental for the Synthesis of Lactam StartingMaterials

Example C5, Step 1

A solution of the amine (e.g., tert-butyl5-(aminomethyl)-2,2-dimethylpyrrolidine-1-carboxylate, 4 g),2-chloroacetyl chloride (4 mL, excess amount) and iPr₂NEt (5 mL) inCH₂Cl₂ was stirred at room temperature until the reaction was complete(approximately 2 h). The reaction was concentrated under reducedpressure, and the desired amide-containing product was purified bycolumn chromatography.

Example C5, Step 3

A solution of the starting material (e.g.,2-chloro-N-((5,5-dimethylpyrrolidin-2-yl)methyl)acetamide (crude,synthesized according to Example F3) K₂CO₃(3.0 g, 21.6 mmol, based on9.9 mmol of starting material used in the previous step) and catalyticamount of NaI in CH₃CN was stirred at 80° C. until the reaction wascomplete (approximately 3 h). Then the suspension was quenched withwater and extracted with CH₂Cl₂. The organic layer was concentrated togive the desired lactam product (e.g.,6,6-dimethylhexahydropyrrolo[1,2-a]pyrazin-3(4H)-one, 1.5 g).

Example C6: General Experimental for the Synthesis of Lactam StartingMaterials

Example C6, Step 1

To a solution of diisopropyl amine (54 mmol) in anhydrous THF (70 mL)was added 2.5 N n-BuLi in hexanes (21 mL, 52 mmol) at approximately −35°C. The solution was stirred at 0° C. for 30 min., and was then cooled to−78° C. Iosbutyronitrile (58 mmol) was slowly introduced, and thereaction mixture was stirred at −78° C. for additional 2 h. The solutionof ethyl acrylate (2.9 g, 29 mmol) in anhydrous THF (15 mL) was addedslowly, and the reaction was stirred at −78° C. until the reaction wascomplete (approximately 50 min). The reaction mixture was then pouredinto NH₄Cl (sat.) aqueous solution (and diluted with MTBE. The organiclayer was washed with water and brine and concentrated. The resultingwas purified by silica gel column chromatography to provide thecyano-ester product (e.g. ethyl 4-cyano-4-methylpentanoate).

Example C6, Step 2

The mixture of the cyano-ester starting material (e.g., ethyl4-cyano-4-methylpentanoate, 30 mmol) and PtO₂ (65 mg) in AcOH (10 mL)was purged with N₂ three times, then subjected to hydrogen gas to at 80to 120 Psi until hydrogen uptake stopped. The catalyst was filtered andrinsed with EtOAc. The filtrate was slowly added into 6N NaOH (aq), thendiluted with EtOAc. The aqueous layer was extracted with additionalEtOAc. The combined organic layer was washed with brine and concentratedto give the desired lactam product (e.g. 5,5-dimethylpiperidin-2-one,84% yield).

General Example D: Synthesis of substituted 2-amino-4-bromobenzoic acidsand 2-amino-4-chlorobenzoic acids Example D1. General Experimental forthe Synthesis of Substituted 2-Amino-4-Bromobenzoic Acids and2-Amino-4-Chlorobenzoic Acids

Example D1, Step 1

A mixture of the 2-amino-4-bromobenzoic acid (e.g.,3-bromo-2-fluoroaniline, 1 equiv) in cone. HCl (approximately 0.45mL/mmol benzoic acid) and water (approximately 0.09 mL) was heated untilit became a clear solution. Subsequently, 2,2,2-trichloroethane-1,1-diol(1.1 equiv) and Na₂SO₄ (7.7 equiv) were pre-warmed to 50° C. and addedto the mixture. The mixture was then stirred, and a solution ofhydroxylamine hydrochloride (3 equiv) in water was added dropwise. Theresulting mixture was refluxed until complete (approximately 1 hour).After cooling to room temperature, the insoluble solid was filtered andwashed with excess water, then evaporated to obtain the desired, crudehydroxyimino acetamide (e.g.,(E)-N-(3-bromo-2-fluorophenyl)-2-(hydroxyimino)acetamide), which wasused in the next step.

Example D1, Step 2

The hydroxyimino acetamide starting material (e.g.,(E)-N-(3-bromo-2-fluorophenyl)-2-(hydroxyimino)acetamide, 1 equiv) wasslowly added to a solution of cone. H₂SO₄ (3.9 mL/mmol startingmaterial) in an ice bath. The reaction mixture was maintained below 50°C. during addition. After addition was complete, the solution was heatedto 90° C. until the reaction was complete (approximately 1 hour). Aftercooling to room temperature, the mixture was poured into ice water andstirred vigorously for 1 hour. The 6-bromoindoline-2,3-dione (e.g.,6-bromo-7-fluoroindoline-2,3-dione) product was filtered and washed withwater, evaporated to obtained crude that was used directly in the nextstep.

Example D1, Step 3

To a solution of the 6-bromoindoline-2,3-dione (e.g.,6-bromo-7-fluoroindoline-2,3-dione, 1 equiv) in 1 N NaOH (0.14 M) wasadded H₂O₂(1.8 M) dropwise and the resulting mixture was stirred at roomtemperature until the reaction was complete (approximately 2 hours). Themixture was filtered and the filtrate was acidified to pH 2 withhydrochloric acid. The precipitate that formed was filtered, washed withwater, and concentrated to provide the 2-amino-4-bromobenzoic acid(e.g., 2-amino-4-bromo-3-fluorobenzoic acid).

General Example E: Fluorination Chemistry Example E1. GeneralExperimental for the Conversion of an Alcohol to Group to a Fluoro Group

To a stirred solution of the alcohol (e.g.,6-bromo-2-(2-hydroxypropan-2-yl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one,1 equiv) in CH₂C₂ was added excess DAST under N₂ at room temperature.The mixture was stirred until it was complete (approximately 3 hours).The reaction mixture was quenched with water and extracted with ethylacetate. The combined organic layers were dried over Na₂SO₄ andconcentrated under reduced pressure. The crude was purified by silicagel chromatography to obtain the desired fluoro-containing product(e.g.,6-bromo-2-(2-fluoropropan-2-yl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one).

Example E2. General Experimental for the Conversion of a Keto Group to aDifluoro Group

To a solution of ketone starting material (e.g., 1-tert-butyl 2-methyl4-oxopyrrolidine-1,2-dicarboxylate, 0.75 g) in CH₂C₂(0.03 M) was addedDAST (approximately 57 equiv) dropwise under N₂ atmosphere. Theresulting mixture was stirred at room temperature overnight or until thereaction was complete. The reaction mixture was washed with H₂O andextracted with CH₂Cl₂. The combined organic layers were dried overNa₂SO₄, then concentrated under reduced pressure to give the desireddifluoro-substituted product (e.g., 1-ter-butyl 2-methyl4,4-difluoropyrrolidine-1,2-dicarboxylate.

Example E3. General Experimental for the Synthesis of Substituted2-Amino-4-Bromobenzoic Acids

The solution of the starting material (e.g.,6-bromo-2,2-dimethyl-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one, 1equiv) and Selectfluor (approximately 1.5 equiv) in DMF (approximately0.07 M) was stirred at approximately 90 OC until the reaction wascomplete (approximately 3 h). The reaction was then cooled to roomtemperature, diluted with H₂O, and extracted with EtOAc. The organiclayers were washed with brine and dried over Na₂SO₄. After the crude wasconcentrated under reduced pressure, and the residue was purified bycolumn chromatography to give the desired fluoro-substituted product(e.g.,6-bromo-3-fluoro-2,2-dimethyl-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one).

Example E4. General Experimental for Fluorination α- to a KetoneCarbonyl

To a solution of the ketone (e.g., tert-butyl4,4-dimethyl-2-oxopyrrolidine-1-carboxylate, 1 equiv) 1.9 mmol) in THF(0.2 M) was added fresh LDA (1.3 equiv, 0.5 M in LDA) at −60° C. After 1h, N-Fluorobenzenesulfonimide (1.3 equiv) in THF (0.4 M in NFSI) wasadded slowly, then the temperature was raised to 0° C. The reactionmixture was stirred until the reaction was complete (approximately 0.5h). The reaction was quenched with saturated NH₄Cl, and the residue wasextracted with ethyl acetate. The organic layer was washed with brine,dried over Na₂SO₄ and concentrated to get the crude fluorinated product(e.g., 3-fluoro-4,4-dimethylpyrrolidin-2-one) that was used directly inthe next step.

General Example F: Protection/Deprotection Chemistry Example F1. GeneralExperimental for Fmoc Protection of an Alcohol

To a stirred solution of the alcohol starting material (e.g.,8-methyl-1,4-dioxaspiro[4.5]decan-8-ol, 1 equiv) and excess pyridine inCH₂Cl₂ (0.1 M) was added (9H-fluoren-9-yl)methyl carbonochloridate (2equiv). The mixture was stirred at room temperature until the reactionwas complete (approximately 2 h). The reaction mixture was then quenchedwith hydrochloride (1 M) and extracted with ethyl acetate. The organicphase was dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to give the desired Fmoc-protected alcohol (e.g.,(9H-fluoren-9-yl)methyl 8-methyl-1,4-dioxaspiro[4.5]decan-8-ylcarbonate).

Example F2. General Experimental for Ketal Deprotection

A solution of the starting ketal (e.g., (9H-fluoren-9-yl)methyl8-methyl-1,4-dioxaspiro[4.5]decan-8-yl carbonate, 1 equiv) andhydrochloric acid (4 M) in THF (0.02 M) was refluxed for 3 h. Aftercooling to room temperature, the mixture was extracted with ethylacetate. The organic phase was dried over anhydrous Na₂SO₄, andconcentrated under reduced pressure to provide the desired ketoneproduct (e.g., (9H-fluoren-9-yl)methyl (1-methyl-4-oxocyclohexyl)carbonate).

Example F3. General Experimental for N-Boc Deprotection

A mixture of the Boc-protected amine starting material (e.g.,2-(2-methoxy-2-oxoethyl)-2-methylpyrrolidine-1-carboxylate, 1 equiv),TFA (1.2 M) and CH₂Cl₂ (0.44 M) was stirred at room temperature untilthe reaction was complete (approximately 4 h). After the solution wasconcentrated, the residue was redissolved in CH₂Cl₂ and treated withEt₃N at 0° C. until pH>7. Then the solution and Et₃N were evaporated togive the crude product (e.g., methyl 2-(2-methylpyrrolidin-2-yl)acetate)which was used for the next step without further purification.

Example F4. General Experimental for Fmoc Deprotection

A solution of the Fmoc-containing starting material (e.g.,(9H-fluoren-9-yl)methyl(3-bromo-8-methyl-12-oxo-6,7,8,9,10,12-hexahydropyrido[3′,2′:4,5]pyrimido[1,2-a]azepin-8-yl)carbonate, 1 equiv) and Et₃N (0.07 M) in CH₂Cl₂ (0.02 M) was stirred atroom temperature overnight or until the reaction was complete. Themixture was concentrated under reduced pressure and purified by silicagel chromatography to give the desired deprotected amine (e.g.,3-bromo-8-hydroxy-8-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrimido[1,2-a]azepin-12(6H)-one).

Example F5. General Experimental for Boc Protection

To a solution of the amine or amide-containing starting material (e.g.,4,4-dimethylpyrrolidin-2-one, 1 equiv, 8.9 mmol) in 1,4-dioxane (0.4 M)was added 4-dimethylamninopyridine (1.2 equiv) and (Boc)₂O (1.2 equiv).The reaction mixture was stirred for 45° C. until the reaction wascomplete (approximately 2 h). Then the mixture was diluted with H₂O andextracted with ethyl acetate. The organic layers were washed with 3 MHCl, brine, dried over Na₂SO₄ and concentrated to give the desiredBoc-protected product (e.g., tert-butyl4,4-dimethyl-2-oxopyrrolidine-1-carboxylate).

Example F6. General Experimental for Boc Protection

A solution of the amine (e.g., azepan-4-one HCl salt, 1 equiv), Na₂CO₃(2 equiv) and (Boc)₂O (1.1 equiv) in 1,4-dioxane (0.7 M) and H₂O (3.3 M)was stirred at room temperature until the reaction was complete. Themixture was diluted with water and extracted with ethyl acetate. Theorganic phase was dried over anhydrous Na₂SO₄ and concentrated underreduce pressure to give the desired Boc-protected product (e.g.,tert-butyl 4-oxoazepane-1-carboxylate).

Example F7. General Experimental for Cbz Deprotection

General Scheme:

A mixture of the Cbz protected amine (e.g., benzyl7,7-difluoro-1-methyl-3-azabicyclo[4.1.0]heptane-3-carbo-xylate) and 10%Pd/C (catalytic amount) in MeOH was stirred at room temperature underhydrogen atmosphere overnight. The mixture was filtered and the filtratewas evaporated under reduced pressure to give the amine (e.g.,7,7-difluoro-1-methyl-3-azabicyclo[4.1.0]heptane).

General Example G: Various Functional Group Interconversions Example G1.General Experimental for the Esterification of a Carboxylic Acid

A solution of carboxylic acid starting material (e.g.,1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylic acid, 1 equiv),CH₃I (2.5 equiv) and K₂CO₃(2.0 equiv) in acetone (0.23 M) was refluxeduntil the reaction was complete (approximately 2 h). After cooling toroom temperature, the reaction mixture was filtered and acetone wasdistilled off under reduced pressure. Then ethyl acetate was added intothe residue and the organic phase was washed with brine, dried overanhydrous sodium sulfate and concentrated under reduced pressure to givethe desired ester product (e.g., 1-tert-butyl 2-methyl4-oxopyrrolidine-1,2-dicarboxylate).

To a solution of a benzyl chloride or a benzyl bromide (e.g.,3-(chloromethyl)-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one, 1 equiv), sodium acetate (10 equiv) in DMF wasstirred at 90° C. for 3 h. After the reaction was cooled to roomtemperature, the reaction mixture was diluted with water and extractedwith ethyl acetate. The combined organic layers were washed with water,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure togive the ester (e.g.,(8,8-dimethyl-11-oxo-7,8,9,11-tetrahydro-6H-pyrido[2,1-b]quinazolin-3-yl)methylacetate).

Example G2. General Experimental for the Hydrolysis of an Ester to aCarboxylic Acid

To a solution of the ester (e.g., 1-tert-butyl 2-methyl4,4-difluoropyrrolidine-1,2-dicarboxylate, 1 equiv) in MeOH (0.22 M) andH₂O (0.65 M) was added LiOH.H₂O (4.0 equiv) at room temperature. Theresulting mixture was stirred until the reaction was complete(approximately 2.5 h). The MeOH was evaporated and the residue mixturewas extracted with diethyl ether (3×100 mL). The combined aqueous layerswere acidified to pH ˜3 with hydrochloric acid (1 M) and extracted withethyl acetate. The combined organic layers were dried over anhydroussodium sulfate, concentrated under reduced pressure to give the desiredcarboxylic acid-containing compound (e.g.,1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidine-2-carboxylic acid).

Example G3. General Experimental for the Conversion of a Methyl Ester toa Primary Amide

To a sealed tube was added the methyl ester starting material (e.g.,methyl 6-bromo-9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline-2-carboxylate, 1 equiv) and excess NH₃/MeOH solution. Themixture was stirred at approximately 80° C. until the reaction wascomplete (approximately 5 h). After cooling to room temperature, themixture was concentrated under reduced pressure to give the desiredamide product (e.g., 6-bromo-9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline-2-carboxamide).

Example G4. General Experimental for the Conversion of an Amide to aNitrile

A solution of the amide starting material (e.g.,6-bromo-9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline-2-carboxamide,1 equiv) and excess POCl₃ in toluene was refluxed until the reaction wascomplete (approximately 2 h). After cooling to room temperature, themixture was poured into water and extracted with ethyl acetate. Thecombined organic phase was dried over Na₂SO₄ and concentrated underreduced pressure to give the desired carbonitrile product (e.g.,6-bromo-9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline-2-carbonitrile).

Example G5. General Experimental for Two Step Carbon Homologation

Example G5, Step 1

Under N₂ atmosphere, the carboxylic acid (e.g.,1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid, 1 equiv)was dissolved in dry THF (0.3 M) and cooled to −30° C., then Et₃N (1.1equiv) was added. To the solution was added isobutyl carbonochloridate(1.1 equiv) dropwise. After stirring for 3 hours, CH₂N₂ (prepared from6.4 equiv of N,4-dimethyl-N-nitrosobenzenesulfonamide and 24 equiv KOH)in ether (1.8 M in KOH) was added and the resulting mixture was stirredat 0° C. overnight or until the reaction was complete. The reactionmixture was quenched with several drops of acetic acid. Afterevaporation of the solvent, the residue was dissolved in ethyl acetate.The organic layers were washed with aqueous NaHCO₃. Then the combinedorganic layers were dried over Na₂SO₄ and concentrated under reducedpressure to give the crude product (e.g., tert-butyl2-(2-diazoacetyl)-2-methylpyrrolidine-1-carboxylate) which waspurification by column chromatography.

Example G5, Step 2

PhCOOAg in Et₃N (0.3 M in PhCOOAg) was added dropwise to the solution ofthe diazo starting material (e.g., tert-butyl2-(2-diazoacetyl)-2-methylpyrrolidine-1-carboxylate, 1 equiv) in MeOH(0.26 M) at −35° C. under nitrogen atmosphere. Then the mixture reactionwas stirred until the reaction was complete, and the temperature wasallowed to warm to room temperature slowly. The solution was evaporatedand the residue was dissolved in ethyl acetate. After filtration throughCelite, the filtrate was concentrated to give the crude product (e.g.,tert-butyl 2-(2-methoxy-2-oxoethyl)-2-methylpyrrolidine-1-carboxylate)which was purified by column chromatography.

Example G6. General Experimental for Grignard Addition to an Ester

To a solution of the ester starting material (e.g., methyl6-bromo-9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline-2-carboxylate,1 equiv) (obtained from 2-amino-4-bromobenzoic acid and methyl5-oxopyrrolidine-3-carboxylate according to Example B1) in dry THF wasadded the Grignard reagent (e.g., CH₃MgBr, 2 equiv) at approximately 0°C. and the resulting mixture was stirred until the reaction was complete(approximately 4 hours). The mixture was quenched with NH₄Cl aqueous andextracted with ethyl acetate, dried over Na₂SO₄ and concentrated underreduced pressure to give the desired product (e.g.,6-bromo-2-(2-hydroxypropan-2-yl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one).

Example G7. General Experimental for Reduction of a Ketone

A solution of the ketone starting material (e.g.,3-bromo-6,7,9,10-tetrahydropyrido[3′,2′:4,5]pyrimido[1,2-a]azepine-8,12-dione,1 equiv), and NaBH₄ (2 equiv) in THF (0.07 M) was stirred at roomtemperature until the reaction was complete (approximately 0.5 h). Thereaction mixture was quenched with water and extracted with ethylacetate. The combined organic layers were dried over Na₂SO₄. Afterfiltration and concentration, the residue was purified by silica gelchromatography to give the desired alcohol product (e.g.,3-bromo-8-hydroxy-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrimido[1,2-a]azepin-12(6H)-one).

Example G8. General Experimental for Grignard Addition to a Ketone

To a solution of the ketone starting material (e.g.,1,4-dioxaspiro[4.5]decan-8-one, 1 equiv) in dry THF was added CH₃MgBr(1.1 equiv) at 0° C. until the reaction was complete (approximately 4h). The mixture was quenched with NH₄Cl aqueous and extracted with ethylacetate, dried over Na₂SO₄ and concentrated under reduced pressure togive the desired alcohol product (e.g.,8-methyl-1,4-dioxaspiro[4.5]decan-8-ol).

Example G9. General Experimental for Alkylation α- to a Ketone

A solution of the ketone or ester starting material (e.g.,1,4-cyclohexanedione monoethylene acetal, 1 equiv), in dry THF (0.64 M)was added dropwise to lithium diisopropylamide (1 equiv) and stirred for2 hours at 0° C. under N₂ atmosphere. A solution of the alkyl halide(e.g., CH₃I, 1.2 equiv) in dry THF (0.8 M in CH₃I) was added dropwise tothe reaction mixture at −78° C. and stirred overnight at roomtemperature. The reaction mixture was quenched with NH₄Cl solution andextracted with ethyl acetate. The combined organic layers were driedover Na₂SO₄. After filtration and concentration, the residue waspurified by silica gel chromatography to give the desired alkylatedproduct (e.g., 7-methyl-1,4-dioxaspiro[4.5]decan-8-one).

Example G10. General Experimental for the Addition of an Amine to MethylAcrylate

The amine (e.g., methyl 2-(2-methylpyrrolidin-2-yl)acetate was dissolvedin methyl acrylate and refluxed until the reaction was complete. Thenthe solution was evaporated and the residue was purified by columnchromatography to the desired product (e.g., methyl3-(2-(2-methoxy-2-oxoethyl)-2-methylpyrrolidin-1-yl)propanoate).

Example G11. General Experimental for the Dieckmann Condensation of aDiester

To a solution of diester starting material (e.g., methyl3-(2-(2-methoxy-2-oxoethyl)-2-methylpyrrolidin-1-yl)-propanoate, 1equiv) in dry THF (0.16 M) and drops of MeOH was added NaH (5.0 equiv,60% in oil) at room temperature. MeOH was added to quench the reactionafter the reaction was stirred overnight. Then the solution wasconcentrated to give the α-keto ester desired product (e.g., methyl8a-methyl-7-oxooctahydroindolizine-6-carboxylate), which was used forthe next step without further purification.

Example G12. General Experimental for Decarboxylation of an Ester

The ester starting material (e.g., methyl8-methyl-7-oxooctahydroindolizine-6-carboxylate) was dissolved in 4M HCland refluxed until the reaction was complete (approximately 3 h). Afterthe mixture was cooled to room temperature, K₂CO₃ was added carefullyuntil the pH=10. Then the solution was extracted with CH₂Cl₂ (6×50 mL).The organic layers were combined, dried over Na₂SO₄, filtered andconcentrated to give the desired decarboxylated product (e.g.,8a-methylhexahydroindolizin-7(1H)-one).

Example G13. General Experimental for Alkylation of an Alcohol

A solution of alcohol starting material (e.g.,6-bromo-2-(2-hydroxypropan-2-yl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one,1 equiv) and sodium hydride (approximately 3 equiv) in THF(approximately 0.03 M) was refluxed for approximately 0.5 h. Thereaction was then cooled to room temperature, and an alkyl halide (e.g.,iodomethane, approximately 2 equiv) was added to the mixture. Themixture was heated at reflux until the reaction was complete(approximately 2 h). The reaction was then cooled to room temperature,quenched with water, and extracted with ethyl acetate. The organic phasewas dried over anhydrous Na₂SO₄, concentrated under reduced pressure togive the desired ether product (e.g.,6-bromo-2-(2-methoxypropan-2-yl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one).

Example G14. Experimental for Elimination of an Alcohol

To a solution of3-bromo-8-hydroxy-8-methyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one)in CH₂Cl₂ was added excess DAST under N₂ at room temperature. Themixture was stirred at the room temperature until the reaction wascomplete (approximately 3 h). The reaction mixture was quenched withwater and extracted with ethyl acetate. The combined organic layers weredried over Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by silica gel chromatography to obtain the desiredalkene-containing product (e.g.,3-bromo-8-methyl-6H-pyrido[2,1-b]quinazolin-11(7H)-one).

Example G15. General Experimental for Oxidation of an Alcohol to anAldehyde or a Ketone

Pyridinium chlorochromate (1 equiv) was suspended in CH₂Cl₂ (0.002 M) atroom temperature and alcohol (e.g., 3-methoxypropanol, 1 equiv) wasrapidly added. When the reaction was complete (approximately 2 h), thereaction was diluted with diethyl ether, the solvent was decanted andthe solid was washed twice with diethyl ether. The organic solvent waswashed with water, brine, and dried over Na₂SO₄. The organic layer wasconcentrated under reduced pressure to give the crude product (e.g.,3-methoxypropanal), which was used in the next step.

Example G16. General Experimental for Oxidation of an Alcohol to anAldehyde or a Ketene

To a solution of alcohol (e.g.,3-bromo-8-hydroxy-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11 (7H)-one, 1equiv) in THF (0.11 M) and CH₂Cl₂ (0.17 M) at 0° C. was addedDess-Martin reagent (DMP) (2 equiv). The resulting mixture was stirredat room temperature until the reaction was complete (approximately 3 h).60 mL of aqueous Na₂S₂O₃ was then added, and the mixture was extractedwith ethyl acetate and dried over Na₂SO₄. After filtration andconcentration, the desired ketone product (e.g.,3-bromo-6H-pyrido[2,1-b]quinazoline-8,11 (7H,9H)-dione) was obtained,which was directly used for the next step without further purification.

Example G17. General Experimental for Reduction of an Ester to anAldehyde

To a solution of the ester starting material (e.g., 1-tert-butyl2-methyl 5,5-dimethylpyrrolidine-1,2-dicarboxylate, 1 equiv) (4.8 g,18.7 mmol) in toluene at −78° C. was added DIBAL-H (37.4 mmol, 1.7mol/L) dropwise, maintaining the temperature below −65° C. The reactionwas stirred at −78° C. until the reaction was complete (approximately 2h) and then quenched with methanol (10 mL). The mixture was then dilutedwith ethyl acetate, saturated NH₄Cl was added, and the mixture wasstirred vigorously for 20 min at room temperature. The two phases werethen separated and the aqueous layer was extracted with CH₂Cl₂. Thecombined organics were then washed with brine, dried over Na₂SO₄,concentrated under reduced pressure and purified by columnchromatography to give the desired aldehyde-containing (e.g., tert-butyl5-formyl-2,2-dimethylpyrrolidine-1-carboxylate, 5 g) product.

Example G18. General Experimental for Reductive Amination of an Aldehyde

To a saturated ammonia MeOH solution, the starting amine (e.g.,tert-butyl 5-formyl-2,2-dimethylpyrrolidine-1-carboxylate, 22 mmol) and10% Pd/C (2 g) was added and stirred under hydrogen atmosphere at roomtemperature until the reaction was complete. The catalyst was removed byfiltration, then the filtrate was concentrated under reduced pressure togive the crude desired amine-containing product (e.g., tert-butyl5-(aminomethyl)-2,2-dimethylpyrrolidine-1-carboxylate), which was usedfor the next step without further purification.

Example G19. General Experimental for O-Demethylation

A solution of the methyl ester (e.g.,3-methoxy-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one,1 equiv) in hydrobromic acid (0.06 M) and acetic acid (0.12 M) wasstirred at reflux until the reaction was complete. The mixture wasdiluted with water and extracted with ethyl acetate. The organic phasewas dried over anhydrous Na₂SO₄ and concentrated under reduced pressure.The crude was purified by silica gel chromatography to give the desiredalcohol product (e.g.,3-hydroxy-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one).

Example G20. General Experimental for Conversion of an Alcohol to theCorresponding Mesylate

To a stirred solution of the alcohol starting material (e.g.,1-(pyridin-2-yl)ethanol, 4.1 mmol) and Et₃N (1.1 mL) in CH₂Cl₂ was addedMsCl (0.5 mL) under N₂ in ice bath. The mixture was stirred at the sametemperature until the reaction was complete (approximately 0.5 h). Thereaction mixture was quenched with water and extracted with ethylacetate. The combined organic layers were dried over Na₂SO₄ andconcentrated under reduced pressure to yield the crude mesylate product(e.g., 1-(pyridin-2-yl)ethyl methanesulfonate, 1.1 g).

Example G21. General Experimental for the Alkylation of an Aromatic orHeteroaromatic Alcohol

A solution of the starting alcohol (e.g.,3-hydroxy-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one,0.41 mmol), K₂CO₃ (3 equiv) and the alkyl halide (e.g.,2-(chloromethyl)pyridine, 1.1 equiv) in DMF (0.05 M in alkyl halide) wasstirred at 120° C. until the reaction was complete (approximately 2 h).The mixture was diluted with water and extracted with ethyl acetate. Theorganic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude mixture was purified by silica gelchromatography to give the desired ether product (e.g.,8,8-dimethyl-3-(pyridin-2-ylmethoxy)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one,80 mg).

A solution of the alcohol (e.g.,3-hydroxy-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one,0.41 mmol), K₂CO₃(2 equiv) and the mesylate starting material (e.g.,1-(pyridin-2-yl)ethyl methanesulfonate, 2.4 equiv) in DMF (0.07 M inmesylate) was stirred at 120° C. until the reaction was complete(approximately 2 h). The mixture was diluted with water and extractedwith ethyl acetate. The organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The crude mixture was purifiedby silica gel chromatography to give the desired ether product (e.g.,8,8-dimethyl-3-(1-(pyridin-2-yl)ethoxy)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one,80 mg).

A solution of the alcohol (e.g.,3-hydroxy-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one,1 equiv), the aryl halide (e.g., 2-iodopyridine, 1.5 equiv),1,10-phenanthroline (0.15 equiv), Cs₂CO₃ (1.5 equiv) and CuI (0.15equiv) in DMSO was stirred in a sealed tube at 90° C. for 3.5 hours. Thereaction was cooled to room temperature, then the reaction mixture wasdiluted with H₂O and extracted with EtOAc. The combined organic layerswere washed with brine and dried over anhydrous sodium sulfate. Afterconcentration under reduced pressure, the residue was purified by silicagel chromatography (EtOAc:n-hexane=1:3) to give the desired etherproduct (e.g.,8,8-dimethyl-3-(pyridin-2-yloxy)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one).

To a solution of alcohol (e.g., pyridin-2-ylmethanol, 2 equiv) intoluene at 100° C. was added 60% NaH in mineral oil (4 equiv). Theresulting solution was stirred for 1 h. To the mixture was added thebenzyl chloride (e.g.,3-(chloromethyl)-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one, 1 equiv) and kept at 100° C. for 2 h.

After cooling to room temperature, the mixture was diluted with waterand extracted with ethyl acetate. The combined organic layers wereconcentrated and purified by column chromatography on silica gel to give6.5 mg of the desired ether product (e.g.,8,8-dimethyl-3-((pyridin-2-ylmethoxy)methyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one).

A solution of alcohol (e.g.,3-(hydroxymethyl)-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one, 1 equiv) aryl bromide or aryl chloride (e.g.,2-chloropyridine, 1.6 equiv), KOH (3.3 equiv) and 18-crown-6(0.01 equiv)in toluene was healed to reflux for 2 h. The reaction mixture was thencooled to room temperature and partitioned between ethyl acetate andwater. The organic layers were washed with brine, dried over Na₂SO₄,filtered, concentrated under vacuum and purified by silica columnchromatography to give the desired other product (e.g.,8,8-dimethyl-3-((pyridin-2-yloxy) methyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one).

Example G22. General Experimental for the Olefination of a Ketone

Wittig olefination of tert-butyl 3-oxopiperidine-1-carboxylate totert-butyl 3-methylenepiperidine-1-carboxylate can be achieved by theprocedures described by Beak, Peter, Lee, Burnell. et al. in Journal ofOrganic Chemistry 1989, 54(2), 458-64.

Example G23. General Experimental for the Cyclopropanation of an Olefin

Cyclopropanation of the olefin can be effected by various modificationsof Simmons-Smith reaction as described by O. Irie et al. in Bioorg. Med.Chem. Lett. 2008, 18, 4642-46460 or by A. B. Charette, A. Beauchemin etal. in Journal of Organometallic Chemistry. 2001, 617-618 702-708.

To a solution of KOH (119 equiv) in H₂O and ethanol heated to 65° C. wasadded N-methyl-N-nitroso-p-toluenesul-fonamide (3 equiv) in ether. Thediazomethane ether solution was distillated and collected at −78° C.Then, a solution of vinyl-containing material (e.g.,8,8-dimethyl-3-(2-(pyridin-2-yl)vinyl)-8,9-dihydro-6H-pyrido[2,1-b]-quinazolin-11(7H)-one,1 equiv) and Rh(OAc)₂ (0.1 equiv) in CH₂Cl₂ was added to the etherealdiazomethane solution and stirred overnight at room temperature. Themixture was quenched with 10% acetic acid in ethyl acetate, diluted withH₂O and extracted with EtOAc. The combined organic layers were washedwith brine, dried over Na₂SO₄. After filtration and concentration, theresidue was purified by column chromatography (EtOAc:n-hexane=1:3) togive the cyclopropanated product (e.g.,8,8-dimethyl-3-(2-(pyridin-2-yl)cyclopropyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one).

Example G24. General Experimental for the Cyclopropanation of an Olefin

Difluorocyclopropanation from tert-butyl5,6-dihydropyridine-1(2H)-carboxylate to tert-butyl7,7-difluoro-3-azabicyclo[4.1.0]heptane-3-carboxylate can be achieved bythe procedures described by Stanislaw F. Wnuk et al. (Journal ofFluorine Chemistry, 130 (2009), 321-328) using an “acid free”trimethylsilyl 2-fluorosulfonyl-2,2-difluoroacetate (TFDA) in anhydrousbenzene containing catalytic amount of dried NaF at under heating, or bythe chemistry with sodium chlorodifluoroacetate in diglyme under heating(WO 2005/079798, p 37) or by the chemistry described by Chun Cai et al.in Chemistry letters, Vol. 34, No. 10, 2005, using sodiumtrifluoroacetate with and AIBN in DMF at 150-180° C.

Example G25. General Experimental for Reduction of Alcohols to Alkanes

Reductive cleavage of tertial allylic alcohol to the correspondingalkane can be effected by the procedure described in WO 2008/124922,example 16, compound 79, page 118.

Example G26. General Experimental for Carbonyl Chloride Formation fromAcid

A solution of the carboxylic acid (e.g.,8,8-dimethyl-11-oxo-7,8,9,11-tetrahydro-6H-pyrido[2,1-b]quinazoline-3-carboxylicacid, 0.54 mmol) in SOCl₂ (8 mL) was stirred at reflux until thereaction was complete (approximately 5 h). The excess SOCl₂ was thenremoved under reduced pressure. The crude carbonyl chloride product(e.g.,8,8-dimethyl-11-oxo-7,8,9,11-tetrahydro-6H-pyrido[2,1-b]quinazoline-3-carbonylchloride) was used without further purification for the next step.

Example G27. General Experimental for Amide Formation from CarbonylChloride

The crude carbonyl chloride (e.g.,8,8-dimethyl-1-oxo-7,8,9,11-tetrahydro-6H-pyrido[2,1-b]quinazoline-3-carbonylchloride) from Example G2 was dissolved in anhydrous THF and added to asolution of the aromatic amine (0.81 mmol) in CHCl₃ (10 mL). Thereaction was stirred at room temperature until the reaction was complete(approximately 0.5 h), and then poured into water. The mixture wasextracted with ethyl acetate, and the organic layer was washed withbrine, dried over anhydrous sodium sulfate. After filtration andconcentration, the crude product was purified by silica gelchromatography purification to provide the desired amide product.

Example G28. General Experimental for Amide Formation by Direct Couplingof Carboxylic Acid and Amine

To a solution of the carboxylic acid (e.g.,8,8-dimethyl-11-oxo-7,8,9,11-tetrahydro-6H-pyrido[2,I-b]quinazoline-3-carboxylic acid, 0.22 mmol) and EDCI-HCl (0.42 mmol)in CH₂Cl₂ (10 mL) was added the aromatic amine (0.22 mmol). The mixturewas stirred at room temperature until the reaction was complete(approximately 10 min) and then poured into 2 N HCl. The mixture wasextracted with CH₂Cl₂ (30 mL) and the organic layer was washed withaqueous NaHCO₃, brine, dried over anhydrous sodium sulfate. Afterfiltration and concentration, the crude amide product was purified bypreparative HPLC.

Example G29. General Experimental for ArNO₂ Reduction to ArNH₂

The nitro-containing starting material (e.g.,8,8-dimethyl-3-nitro-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one,0.25 mmol) was dissolved in MeOH (5 mL). To the solution was added acatalytic amount of Pd/C. The reaction mixture was vacuumed and thenback filled with hydrogen gas three times. The solution was stirredunder H₂ (1 atm) for 1 h. The reaction mixture was filtered and washedwith methanol. The filtration was concentrated to give the desired amineproduct (e.g.,3-amino-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one).

Example G30: General Experimental for 1,4-Addition to α,β-UnsaturatedKetones

To a stirred slurry of CuI (0.33 mol, 1.2 equiv) in anhydrous ether (1.5L) at −5 to 0° C. was added dropwise an ethereal solution ofmethylithium (500 mL of 1.31 mol/L, 0.655 mol, 2.4 equiv) over 1.5 h.After additional one hour of stirring, a solution of3-methylcyclopent-2-enone (26 g, 0.27 mol, 1.0 eq) in 150 mL ofanhydrous ether was added dropwise at −5 to 0° C. over 0.5 h. Afterstirring at −5 to 0° C. for 30 min, the reaction mixture was quenchedwith aq. NH₄Cl solution. The mixture was then adjusted pH to 8 withaqueous ammonia and extracted with CH₂Cl₂. The combined organic layerswere washed with brine twice and dried over Na₂SO₄. The solvents wereremoved to ⅕ of the original volume at 15° C. under reduced pressure.The crude product was directly used for the next step.

Example G31. General Experimental for Reduction of a Ester

To a solution of the ester (e.g., methyl3-bromo-8-methyl-11-oxo-7,8,9,11-tetrahydro-6H-pyrido[2,1-b]quinazoline-8-carboxylate, 1 equiv) in THF was added LiBH₄ (5equiv). The reaction was stirred at room temperature for 3 h, then thereaction mixture was diluted with water and extracted with ethylacetate. The combined organic layers were washed with NaHCO₃ solution,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel to give thedesired alcohol (e.g.,3-bromo-8-(hydroxymethyl)-8-methyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one).

Example G32. General Experimental for Amination

A solution of aryl bromide (e.g.,3-bromo-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one,1 equiv), copper powder (1.6 equiv) in excess 33% methylamine ethanolsolution and H₂O was stirred in a sealed tube at 80° C. overnight. Thereaction was cooled to room temperature, then the mixture was dilutedwith water and extracted with ethyl acetate. The organic layers werewashed with brine and dried over Na₂SO₄. After concentration, theresidue was purified by silica gel chromatography to give the amineproduct (e.g.,8,8-dimethyl-3-(methylamino)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one).

A solution of aryl bromide (e.g.,3-bromo-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one,1 equiv), aromatic amine (e.g., pyridin-2-amine, 1.1 equiv), K₂CO₃ (2.3equiv), CuI (0.2 equiv) and N, N-dimethylethane-1,2-diamine (0.5 equiv)in 1,4-dioxane was stirred at 105° C. under N₂ overnight. The reactionwas cooled to room temperature, then the reaction mixture was dilutedwith H₂O and extracted with EtOAc. The combined organic layers werewashed with brine, dried over Na₂SO₄. After filtration andconcentration, the crude product was purified by silica columnchromatography to give the desired product.

A solution of aryl bromide (e.g., 2-bromopyridine, 1.5 equiv), imidazole(e.g., 4-bromo-1H-imidazole, 1 equiv), L-Proline (0.2 equiv), CuI (0.1equiv), K₂CO₃(2 equiv) in DMSO was stirred at 110° C. under N₂overnight. The reaction was cooled to room temperature, then thereaction mixture was diluted with H₂O and extracted with EtOAc. Thecombined organic layers were washed with brine, dried over Na₂SO₄. Afterfiltration and concentration, the crude product was purified columnchromatography (EtOAc:n-hexane=1:3) to give the C—N coupling product(e.g., 2-(4-bromo-1H-imidazol-1-yl)pyridine).

To a stirred solution of the starting amine (e.g., ten-butylpiperazine-1-carboxylate, 1 equiv), Pd(OAc)₂ (0.005 equiv),racemic-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (0.01 equiv),potassium tert-butoxide (1.5 equiv) and 2-bromopyridine (1.2 equiv) intoluene was heated at 90° C. for 1.5 h. The mixture was diluted withwater and extracted with ethyl acetate. The organic phase was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to give the C—N coupling product (e.g., tert-butyl4-(pyridin-2-yl)piperazine-1-carboxylate).

Example G33. General Experimental for Hydrogenation of Olefin or Alkyne

A solution of alkyne or olefin (e.g.,(E)-8,8-dimethyl-3-(3-(pyridin-2-yl)prop-1-enyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-oneand Pd/C (catalytic amount) in EtOH was stirred under H₂ atmosphere at 1atm for 2 h. The reaction mixture was filtered and concentrated underreduced pressure. The crude product was purified by columnchromatography on silica gel to give the alkyl product (e.g.,8,8-dimethyl-3-(3-(pyridin-2-yl)propyl)-6,7,8,9-tetrahydropyrido[2,1-b]quinazolin-11-one).

Example G34. General Experimental for Oxidation of Alkyne to Ketone

To a solution of the alkyne (e.g.,8,8-dimethyl-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one (1 equiv) in 98% H₂SO₄ (100 equiv) wasadded HgSO₄ (0.55 equiv). The mixture was stirred at room temperaturefor 5 h and then quenched with saturated sodium carbonate aqueoussolution. After filtration, the mixture was extracted with EtOAc. Thecombined organic layers were washed with brine, dried over Na₂SO₄. Afterfiltration and concentration, the crude product was purified by columnchromatography (EtOAc:n-hexane=1:3) to give the desired ketone (e.g.,8,8-dimethyl-3-(2-(pyridin-2-yl)acetyl)-6,7,8,9-tetrahydropyrido[2,1-b]quinazolin-1l-one).

Example G35. General Experimental for Hydroxylamination of Nitriles

To a solution of aromatic nitrile (e.g., picolinonitrile, 1 equiv) andNH₂OH.HCl (1.2 equiv) in H₂O was added NaHCO₃ (2.4 equiv) in threeportions. The reaction was stirred at room temperature overnight, thenthe mixture was diluted with H₂O and extracted with ethyl acetate. Thecombined organic layers were washed with brine and dried over Na₂SO₄.After filtration, the solvent was removed to give the desired product(e.g., (Z)—N′-hydroxypicolinamidine).

Example G36. General Experimental for the Synthesis of Azide fromAromatic Chloride or Aromatic Bromide

A solution of aryl bromide or aryl chloride (e.g., chlorobenzene, 1equiv), CuI (0.1 equip), L-Proline (0.3 equiv), NaN₃ (2 equiv) and NaOH(1 equiv) in ethanol/water (7:3 ratio) was heated at reflux overnight.The reaction was cooled to room temperature, then the mixture wasextracted with Et₂O. The combined organic layers were washed with brine,dried over Na₂SO₄. After filtration, the filtrate was concentrated to ⅕volume and directly used for the next step.

Example G37. General Experimental for the Synthesis of Tin

To a solution of the aryl bromide or aryl-H (e.g., benzo[d]oxazole, 1equiv) in anhydrous Et₂O was added n-BuLi (1.06 equiv) slowly at −65° C.The reaction was then stirred at the same temperature for 30 min. Then,chlorotributylstannane tributyltin chloride (1 equiv) was added and themixture was allowed to warm to room temperature and stirred for 1.5 h.After filtration through celite, the filtrate was evaporated. The crudeproduct (e.g., 2-(tributylstannyl)benzo[d]oxazole) was directly used forthe next step without further purification.

Example G38. General Experimental for the Reaction of Aldehyde withAlkyne

To a solution of alkyne (e.g., 2-ethynylpyridine, 3 equip) in THF at rtwas added CH₃MgBr (3 equiv) dropwise over 5 min. The resulting solutionwas stirred for additional 15 min. To the mixture was added the aldehyde(e.g.,8,8-dimethyl-11-oxo-7,8,9,11-tetrahydro-6H-pyrido[2,1-b]quinazoline-3-carbaldehyde,1 equiv) in THF over 10 min and stirred at rt for 1 h. The reactionmixture was diluted with water and extracted with ethyl acetate. Thecombined organic layers were concentrated and purified by columnchromatography on silica gel to give the desired product (e.g.,3-(1-hydroxy-3-(pyridin-2-yl)prop-2-ynyl)-8,8-dimethyl-6,7,8,9-tetrahydropyrido[2,1-b]quinazolin-11-one).

General Example H: Other Synthetic Schemes Example H1 Synthesis of(1S,4R,6S)-6-methoxy-2-azabicyclo[2.2.1]heptan-3-one

Example H1, Step 1

To a solution of cyclopent-3-enecarboxylic acid (5.0 g, 44.6 mmol) inCH₂Cl₂ (50 mL) at 0° C. under argon atmosphere were added oxalylchloride (4.3 mL, 49.1 mmol) and DMF (5 drops). After stirring atambient temperature for 3 h, CH₂Cl₂ (50 mL), pyridine (70 mL),p-methoxybenzylamine (7.6 mL, 58.0 mmol), and 4-dimethylaminopyridine(545 mg, 4.46 mmol) were added to the reaction mixture at 0° C. Thereaction mixture was stirred at ambient temperature for 12 h. Thereaction was quenched with water at 0° C. and extracted by EtOAc. Thecombined organic extracts were washed with water, 1 M aq HCl, brine,dried over Na₂SO₄, filtered through Celite, and evaporated to give thedesired product for the next step. MS (ESI+): m/z 232 (M+H⁺).

Example H1, Step 2

To a solution of the crude N-(4-methoxybenzyl)cyclopent-3-enecarboxamidefrom the last step in CH₂Cl₂ (50 mL) was added m-chloroperbenzoic acid(69 wt %, 13.4 g, 53.5 mmol). After stirring at ambient temperature for4 h, the CH₂Cl₂ was evaporated. The residue was suspended in water andextracted with EtOAc (200 mL×3). The combined organic extracts werewashed with 1 M aq NaOH (100 mL), water (100 mL), brined, dried overNa₂SO₄, filtered through Celite, and evaporated to give the desiredproduct (N-(4-methoxybenzyl)-6-oxabicyclo[3.1.0]hexane-3-carboxamide).MS (ESI+): m/z 248 (M+H⁺).

Example H1, Step 3

To a solution of the crudeN-(4-methoxybenzyl)-6-oxabicyclo[3.1.0]hexane-3-carboxamide from thelast step in t-BuOH (200 mL) was quickly added t-BuOK (10.0 g, 89.2mmol). After stirring at 80° C. for 4 h, the reaction was quenched by aqNH₄Cl and water, and extracted by EtOAc. The combined organic extractswere washed with brine, dried over Na₂SO₄, filtered through Celite, andevaporated. The product ((1S,4R,6S)-6-hydroxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one)was purified by silica gel chromatography (EtOAc/hexane=1:1) (4.7 g). MS(ESI+): m/z 248 (M+H⁺).

Example H1, Step 4

To a solution of the(1S,4R,6S)-6-hydroxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]-heptan-3-one(500 mg, 2.02 mmol) in anhydrous THF (20 mL) was added NaH (60 wt %,4.04 mmol) at room temperature. The mixture was stirred at 40° C. for 30min. After cooling to room temperature, CH₃I (0.41 mL, 8.08 mmol) wasadded. The reaction mixture was stirred for 1 h at ambient temperatureand quenched with water (50 mL), extracted by EtOAc. The combinedorganic extracts were washed with brine, dried over Na₂SO₄, andevaporated to give (1S,4R,6S)-6-methoxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one.MS (ESI+): m/z 262 (M+H⁺).

Example H1, Step 5

A solution of ammonium cerium(IV) (3.3 g, 6.06 mmol) in water (10 mL)was added to(1S,4R,6S)-6-methoxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one(527 mg, 2.02 mmol) in CH₃CN (40 mL). The reaction mixture was stirredat ambient temperature for 2 h and extracted by EtOAc (60 mL). Theorganic extract was washed with water and brine, dried over Na₂SO₄, andevaporated to give the crude(1S,4R,6S)-6-methoxy-2-azabicyclo[2.2.1]heptan-3-one. MS (ESI+): m/z 142(M+H⁺).

Example H2 Synthesis of (3aS,7aR)-hexahydroisobenzofuran-5(1H)-one

Example H2, Step 1

To a solution of lithium aluminum hydride (14 g, 396 mmol) in anhydrousTHF (200 mL) was added(3aR,7aS)-3a,4,7,7a-tetrahydroisobenzofuran-1,3-dione (15 g, 99 mmol) at0° C. under nitrogen atmosphere. The reaction mixture was stirred atroom temperature overnight. After cooling with ice-water, the mixturewas quenched with water (300 mL) and extracted with ethyl acetate (3×400mL). The combined organic layers were washed with brine, dried overNa₂SO₄ and concentrated under reduced pressure to give the crude product(12 g). The crude product was used for the next step without furtherpurification. MS (ESI+): m/z 143 (M+H⁺).

Example H2, Step 2

A solution of (1R,2S)-cyclohex-4-ene-1,2-diyldimethanol (12 g, 8.5mmol), benzene sulfonyl chloride (16 g, 9.3 mmol) andN,N-diisopropylethylamine (21.8 g, 17 mmol) in 1,4-dioxane (200 mL) wasrefluxed overnight. After cooling to room temperature, the mixture wasdiluted with water (500 mL) and extracted with ethyl acetate (3×400 mL).The combined organic layers were washed with brine, dried over Na₂SO₄.After concentration under reduced pressure, the crude product waspurified by silica gel chromatography to give the desired product (7.0g). MS (ESI+): m/z 125 (M+H⁺).

Example H2, Step 3

To a solution of mercuric acetate (10.2 g, 32 mmol) in THF (20 mL) andH₂O (20 mL) was added 3aR,7aS)-1,3,3a,4,7,7a-hexahydroisobenzofuran (2g, 32 mmol) in THF (10 mL) at 0° C. The reaction mixture was stirred atroom temperature overnight. The resulting mixture was cooled to 0° C.,then 29 mL of 3 N sodium hydroxide aqueous solution was added to themixture followed by 29 mL of 0.5 M sodium borohydride in 3N sodiumhydroxide aqueous solution. The mercury was allowed to settle, and thesupernatant liquid was decanted and extracted with ether (3×100 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄ andconcentrated to give the crude product (2.1 g). MS (ESI+): m/z 143(M+H⁺).

Example H2, Step 4

A solution of (3aS,7aR)-octahydroisobenzofuran-5-ol (2.1 g, 14.8 mmol),Dess-Matin periodinane (13 g, 44.4 mmol) in DCM (50 mL) was stirred atroom temperature for 2 h. The reaction mixture was then quenched withNa₂CO₃ aqueous solution (50 mL) and extracted with CH₂Cl₂ (2×100 mL).The combined organic layers were washed with brine, dried over Na₂SO₄and concentrated under reduced pressure to give the crude product (2.0g).

Example H3. Synthesis of (3aS,7aR)-hexahydroisobenzofuran-5(1H)-one

Example H3, Step 1

To a solution of8-bromo-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11 (1H)-one(0.8 g, 2.7 mmol) and K₂CO₃ in acetone (60 mL) was added excess2-bromoethanol. The mixture was stirred at room temperature for 6 h. Themixture was diluted with water and extracted with CH₂C₂(3×60 mL). Thecombined organic layers were dried over Na₂SO₄, filtered, and evaporatedto give 0.7 g of the desired product MS (ESI): m/z 338, 340 (M+H⁺).

Example H3, Step 2

To a solution of8-bromo-3-(2-hydroxyethyl)-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one (0.7 g, 2.1 mmol) and Et₃N in CH₂Cl₂ (60 mL) wasadded benzenesulfonyl chloride. The mixture was stirred at roomtemperature for 2 h. The mixture was diluted with water and extractedwith ethyl acetate (3×60 mL). The combined organic layers were driedover Na₂SO₄, filtered, and evaporated to give 230 mg of the desiredproduct. MS (ESI+): m/z 356, 358 (M+H⁺).

Example H3, Step 3

A solution of8-bromo-3-(2-chloroethyl)-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one (0.2 g, 0.5 mmol) and NaH in THF (10 mL) wasstirred at room temperature overnight. The mixture was diluted withwater and extracted with ethyl acetate (3×20 mL). The combined organiclayers were dried over Na₂SO₄, filtered, and evaporated to give 260 mgof the crude. MS (ESI+): m/z 320, 322 (M+H⁺).

Example H4. Synthesis of (5,5-bis(fluoromethyl)piperidin-2-one

5,5-Bis(fluoromethyl)piperidin-2-one may be synthesized by the chemistrydepicted in the above scheme. Bisalkylation of dimethyl malonate with(Z)-1,4-dichlorobut-2-ene under basic conditions provides dimethylcyclopent-3-ene-1,1-dicarboxylate, which can be transformed into4,4-bis(fluoromethyl)cyclopent-1-ene by LiAlH₄ reduction andDAST-mediated fluorination (Example E1). Hydroboration of the olefinfunctionality followed by Swern oxidation provides the ketone. Treatmentof ketone with NH₂OH provides the oxime intermediate, and Beckmannrearrangement (Example C2) delivers(5,5-bis(fluoromethyl)piperidin-2-one.

Example H5. Synthesis of 1-methylbicyclo[3.1.0]hexan-3-one

Example H5, Step 2

To a solution of 1-(allyloxy)but-2-yne (11.9 g, 0.11 mol) in anhydrousTHF (300 mL) at −65° C. was added n-BuLi (70 mL, 0.175 mol, 2.5 M)slowly under N₂ and the reaction was stirred for 3 h. The reaction wasquenched with H₂O (80 mL) at −65° C., then the mixture was extractedwith Et₂O (3×150 mL). The combined organic layers were washed withbrine, dried over Na₂SO₄. After filtration and concentration, the crudeproduct was purified by silica column chromatography [Et₂O: Petroleumether (30° C.˜60° C.)=1:6] to give the desired product.

Example H5, Step 3

A solution of hept-1-en-5-yn-4-ol (3.8 g, 34.5 mmol) and PtCl₂ (0.5 g,1.88 mmol) in toluene (150 mL) was stirred at 65° C. for 7 h. Afterfiltration, the filtrate was directly used for next step without furtherpurification.

Example H6. Synthesis of Oxadiazole

Example H6, Step 2

To a solution of an aromatic acid ester (e.g., methyl2,2-dimethyl-9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline-6-carboxylate)prepared from Example B1 in ethanol was added excess 80% hydrazinehydrate. The reaction mixture was heated at reflux for 2 h. The reactionwas cooled to room temperature, then the slurry was filtered. Thefiltrate was washed with ethanol twice and was used directly in nextstep.

Example H6, Step 3

A solution of aromatic acid (e.g., picolinic acid) in excess SOCl₂ washeated at reflux for 3 h. Then excess SOCl₂ was removed. The residue wasdissolved in CH₂Cl₂ and added to a solution of a carbohydrazide (e.g.,2,2-dimethyl-9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline-6-carbohydrazide,1.84 mmol) in CH₂Cl₂. Then Et₃N (4 equiv) was added. The reactionmixture was stirred at room temperature for 15 min, poured into H₂O andextracted with CH₂Cl₂. The combined organic layers were washed withbrine, dried over Na₂SO₄. After filtration and concentration, the cruderesidue was purified by preparative chromatography to give the desiredcarbohydrazide (e.g.,2,2-dimethyl-9-oxo-N′-picolinoyl-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline-6-carbohydrazide).

Example H6, Step 4

A solution of carbohydrazide (e.g.,2,2-dimethyl-9-oxo-N′-picolinoyl-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline-6-carbohydrazide)in excess POCl₃ was heated at reflux for 6 h. Then excess POCl₃ was thenremoved. The residue was quenched with saturated sodium carbonatesolution and extracted with EtOAc. The combined organic layers werewashed with brine, dried over Na₂SO₄. After filtration andconcentration, the crude residue was purified by preparativechromatography to give the desired oxadiazole (e.g.,2,2-dimethyl-6-(5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one).

Example H7. Synthesis of Thiadiazole

A mixture of carbohydrazide (e.g.,8,8-dimethyl-11-oxo-N′-picolinoyl-7,8,9,11-tetrahydro-6H-pyrido[2,1-b]quinazoline-3-carbohydrazide,1 equiv) and P₂S₅(8 equiv) in pyridine (0.1 M) was stirred at 70° C. for6 h. The reaction was cooled to room temperature, then the mixture waspoured into H₂O and extracted with EtOAc. The combined organic layerswere washed with brine, dried over Na₂SO₄. After filtration andconcentration, the crude residue was purified by preparativechromatography to give the desired thiadiazole (e.g.,8,8-dimethyl-3-(5-(pyridin-2-yl)-1,3,4-thiadiazol-2-yl)-6,7,8,9-tetrahydropyrido[2,1-b]quinazolin-11-one).

Example H8. Synthesis of Oxadiazole

A solution of an acid (e.g.,8,8-dimethyl-11-oxo-7,8,9,11-tetrahydro-6H-pyrido[2,1-b]quinazoline-3-carboxylicacid, 1 equiv), N′-hydroxypicolinimidamide (1.5 equiv), EDCI (1.5 equiv)and HOBt (1.5 equiv) in DMF was stirred at 80° C. overnight. Thereaction was cooled to room temperature, then the reaction mixture wasdiluted with H₂O and extracted with EtOAc. The combined organic layerswere washed with brine and dried over Na₂SO₄. After filtration andconcentration, the crude residue was purified by preparativechromatography to give the desired oxadiazole-containing product (e.g.,8,8-dimethyl-3-(3-(pyridin-2-yl)-1,2,4-oxadiazol-5-yl)-6,7,8,9-tetrahydropyrido[2,1-b]quinazolin-11-one).

Example H9. Synthesis of 1,2,3-triazole

A solution of the aromatic alkyne (e.g.,3-ethynyl-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one,0.6 mmol), sodium L-ascorbate (3 equiv), saturated CuSO₄ aqueoussolution (0.24 M) and the azide (e.g., azidobenzene in Et₂O solution, 3equiv) in CH₃CN was stirred at room temperature for 4 days. The reactionwas then diluted with H₂O, and the mixture was extracted with ethylacetate. The combined organic layers were washed with brine, dried overNa₂SO₄. After filtration and concentration, the crude residue waspurified by silica column chromatography to give the triazole (e.g.,8,8-dimethyl-3-(1-phenyl-1H-1,2,3-triazol-4-yl)-6,7,8,9-tetrahydropyrido[2,1-b]quinazolin-11-one).

Example H10. Synthesis of 2-bromo-4-(pyridin-2-yl)thiazole

Example H10, Step 1

A solution of 2-bromo-1-(pyridin-2-yl)ethanone hydrobromide (1.0 g, 3.56mmol) and KSCN (410 mg, 4.27 mmol) in acetone (50 mL) was stirred atreflux overnight. The solvent was then removed, and the residue wasdirectly used for the next step.

Example H10, Step 2

To a solution of 1-(pyridin-2-yl)-2-thiocyanatoethanone hydrobromideprepared from step 1 in acetic acid (20 mL) was added 33% HBr in aceticacid (5 mL). The mixture was stirred at 50° C. for 5 h. After adjustingto pH=9 with saturated Na₂CO₃ aqueous solution, the mixture wasextracted with ethyl ether (3×200 mL). The combined organic layers werewashed with brine and dried over Na₂SO₄. After filtration andconcentration, the crude product was purified by silica columnchromatography to give the desired product.

Example H11. Synthesis of 5-bromo-2-(pyridin-2-yl)oxazole

Example H11, Step 1

To a solution of picolinaldehyde (5.0 g, 46.7 mmol) and 2-aminoethanol(3.42 g, 56.1 mmol) in t-BuOH (400 mL) was added K₂CO₃ (19.3 g, 140.1mmol) and iodine (11.8 g, 93.4 mmol). The reaction mixture was heated atreflux overnight. After quenching with saturated Na₂SO₃ aqueoussolution, the mixture was extracted with ethyl ether (8×100 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄. Afterfiltration and concentration, the crude product was purified by silicacolumn chromatography to give the desired product (800 mg).

Example H11, Step 2

To a solution of 2-(pyridin-2-yl)-4,5-dihydrooxazole (710 mg, 4.8 mmol)in CCl₄ (50 mL) was added NBS (2.56 g, 14.4 mmol) and AIBN (40 mg, 0.24mmol). The reaction mixture was stirred at 70° C. overnight. Afterfiltration and concentration, the crude product was purified by silicacolumn chromatography to give the desired product (116 mg).

Example H12. Synthesis of 5-(pyridin-2-yl)oxazole

A mixture of picolinaldehyde (2.3 g, 42.6 mmol), TosMIC (4.4 g, 45.2mmol) and K₂CO₃ (3.4 g, 48.8 mmol) in methanol (70 mL) was reflux for 2h. The reaction was cooled to room temperature, then the mixture wasconcentrated and purified by silica gel column chromatography to givethe desired product (3.05 g).

Example H13. Synthesis of Imidazole Ring

Example H13-A, Step 1

To a mixture of the aromatic aldehyde (e.g., picolinaldehyde 1.0 g, 93mmol) and TosMIC (1.83 g, 93 mmol) in ethanol (20 mL) was added NaCN (20mg). The reaction mixture immediately became clear and then solidseparated out. The reaction was stirred for another 40 min, then themixture was filtered to give a pale yellow solid (2.2 g), which wasdirectly used for the next step.

Example H13-A, Step 2

A mixture 5-(pyridin-2-yl)-4-tosyloxazole (2.2 g, 7.3 mmol) andNH₃/CH₃OH (15 mL) was stirred at 80° C. for 2 days in a sealed tube.After the solvent was removed, the residue was purified by silica columnchromatography (DCM:CH₃OH=2:1) to give the desired product (400 mg).

Example H13-B, Step 1 and 2

A solution of a starting acid (e.g.,8,8-dimethyl-11-oxo-7,8,9,11-tetrahydro-6H-pyrido[2,1-b]quinazoline-3-carboxylicacid, 1 equiv) and KOH (1.1 equiv) in ethanol was stirred at roomtemperature overnight. The solvent was removed to give a buff solid.Then the solid and HBr salt of 2-bromo-1-(pyridin-2-yl)ethanone (1equiv) were dissolved in DMF and stirred at room temperature overnight.The reaction mixture was poured into H₂O and extracted with EtOAc. Thecombined organic layers were washed with brine, dried over Na₂SO₄. Afterfiltration and concentration, the crude ester intermediate (e.g.,2-oxo-2-(pyridin-2-yl)ethyl8,8-dimethyl-11-oxo-7,8,9,11-tetrahydro-6H-pyrido[2,1-b]quinazoline-3-carboxylate)was used directly for next step.

Example H13-B, Step 3

A solution of the crude ester intermediate (e.g.,2-oxo-2-(pyridin-2-yl)ethyl8,8-dimethyl-1-oxo-7,8,9,11-tetrahydro-6H-pyrido[2,1-b]quinazoline-3-carboxylate(1 equip) and CH₃COONH₄ (9 equiv) in acetic acid (0.1 M) was stirred at80° C. overnight. After adjusting to pH=8 with saturated Na₂CO₃, themixture was extracted with EtOAc. The combined organic layers werewashed with brine, dried over Na₂SO₄. After filtration andconcentration, the crude product (e.g.,8,8-dimethyl-3-(4-(pyridin-2-yl)-1H-imidazol-2-yl)-6,7,8,9-tetrahydropyrido[2,1-b]quinazolin-11-one)was purified by preparative chromatography.

Example H14. Synthesis of 2-oxa-6-azaspiro[3.6]decan-7-one

Example H14, Step 5

A solution of ethyl 4-(3-(nitromethyl)oxetan-3-yl)but-2-enoate (600 mg,2.6 mmol) and 10% Pd—C (100 mg) in CH₃COOH (15 mL) was stirred at roomtemperature for 4 h under H₂ atmosphere. After filtration, the filtratewas adjusted pH to 8-9 and extracted with CH₂Cl₂ (4×100 mL). The organiclayers were washed with brine (200 mL) and dried over Na₂SO₄. Afterconcentrated, the residue was purified by silica gel chromatography togive the desired product as a yellow oil (400 mg).

Example H14, Step 6

To a solution of ethyl 4-(3-(aminomethyl)oxetan-3-yl)butanoate (400 mg,2.6 mmol) in ethanol (10 mL) was added aqueous NH₃ (4 mL). The mixturewas stirred in sealed tube at 85° C. for 2 days. The reaction mixturewas concentrated under reduced pressure to give crude product for thenext step without further purification.

Example H14, Step 7

To a solution of 2-amino-4-bromobenzoic acid (200 mg, 0.93 mmol) inbenzene (15 mL) was added SOCl₂ (3 mL). The reaction mixture was heatedat reflux for 2 h and then concentrated under reduced pressure. Thenadditional benzene (10 mL) was added and concentrated to dryness. Thenbenzene (15 mL) and 2-oxa-6-azaspiro[3.6]decan-7-one (100 mg, 0.65) wereadded to the residue and heated at reflux for 3 h. The reaction wascooled to room temperature, then the solution was washed with saturatedaqueous Na₂CO₃ and brine. After concentration, the residue was purifiedby silica gel chromatography to give the desired product (70 mg).

Example H15. Synthesis of hexahydroimidazo[1,5-a]pyridin-3(5H)-one

A solution of CDI (830 mg, 5.1 mmol) and piperidin-2-ylmethanamine (520mg, 4.6 mmol) in DCM (20 mL) was stirred at room temperature overnight.After the solvent was removed, the residue was directly used for thenext step without further purification.

Example H16. Synthesis of Isoxazole

Example H16, Step 2

A solution of an oxime (e.g.,8,8-dimethyl-11-oxo-7,8,9,11-tetrahydro-6H-pyrido[2,1-b]quinazoline-3-carbaldehydeoxime, 1 equiv) prepared from step 1 in CH₃OH and H₂O was added toaromatic alkyne (e.g., 2-ethynylpyridine, 1 equiv) and[bis(trifluoroacetoxy)iodo]benzene (1.2 equiv). The reaction mixture wasstirred at room temperature for 4 h. After diluting with H₂O, themixture was extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over Na₂SO₄. After filtration andconcentration, the crude isoxazole (e.g.,8,8-dimethyl-3-(5-(pyridin-2-yl)isoxazol-3-yl)-6,7,8,9-tetrahydropyrido[2,1-b]quinazolin-11-one)was purified by preparative chromatography.

Example H17. Synthesis of Urea

Example H17, Step 1

To a solution of aromatic acid (e.g., picolinic acid, 8.1 mmol) inacetone and water was added triethylamine (1.5 equiv). The mixture wascooled to 0° C. in a ice-bath. Ethylchloroformate (1.5 equiv) was thenadded and the resulting mixture was stirred at 0° C. for 1.5 h. To themixture was added sodium azide (1.6 equiv), and the mixture was stirredfor another 1.5 h. After the mixture was concentrated, the residue wasdiluted with dichloromethane and washed with water. The organic layerwas dried over Na₂SO₄. After concentrating, the residue was purified bysilica column chromatography to give the desired carboxyl azide (e.g.azido(pyridin-2-yl)methanone).

Example H17, Step 2

A solution of carboxyl azide (e.g., picolinoyl azide, 2 equiv) intoluene (0.7 M) was stirred at 80° C. for 2 h. Then aromatic amine(e.g.,3-amino-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one,1 equiv) was added. The mixture was stirred at 100° C. overnight andthen heated at reflux for 3 h. After the solvent was evaporated, theresidue was purified by preparative chromatography to give the desiredurea (e.g.,1-(8,8-dimethyl-11-oxo-7,8,9,11-tetrahydro-6H-pyrido[2,1-b]quinazolin-3-yl)-3-(pyridin-2-yl)urea).

Example H18. Synthesis of1a-(hydroxymethyl)-8-bromo-1.2.3.10b-tetrahydrocyclopropa[3.4]pyrido[2,1-b]quinazolin-5(1aH)-one

Example H18, Step 1

To a solution of cyclopent-3-ene-1,1-diyldimethanol (6.0 g, 46.8 mmol)in dry THF (120 mL) was added NaH (7.5 g, 187.2 mmol) at 0° C. undernitrogen atmosphere. After 1.5 h, 1-(bromomethyl)-4-methoxybenzene (20.5mL, 140 mmol) was added and the reaction mixture was stirred overnightat it. The reaction mixture was quenched by aq NH₄Cl and extracted withethyl acetate. The organic layers were washed with brine, dried overNa₂SO₄, filtrated and concentrated to give the crude product (30 g)which was used for the nest step without purification.

Example H₁₈, Step 6

A solution of 2-amino-4-bromobenzoic acid (4.32 g, 20.0 mmol), SOCl₂(7.2 mL, 100 mmol) in toluene (300 mL) were stirred for 4 h at 80° C.under nitrogen atmosphere. After the solvent and excess SOCl₂ wereevaporated under reduced pressure, toluene (200 mL) and4,4-bis((4-methoxybenzyloxy)methyl)piperidin-2-one (2.0 g, 5.0 mmol)were added and stirred for 4 h at 70° C. under nitrogen atmosphere. Thenthe mixture was concentrated and redissolved in ethyl acetate, washedwith aq Na₂CO₃, dried over Na₂SO₄, filtrated and concentrated to givethe crude product which was used for the next step without furtherpurification.

Example H18, Step 7

To a solution of3-bromo-7,7-bis((4-methoxybenzyloxy)methyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one(˜5.0 mmol) in DCM (100 mL) and H₂O (12 mL) was added DDQ (4.54 g, 20.0mmol) and the mixture was stirred for 1 h. The reaction mixture waspoured into 2N NaOH, and the organic layer was separated. The aqueousphase was extracted with DCM. The organic layers were combined andwashed with brine, dried over Na₂SO₄, filtered and concentrated to givethe crude product which was purified by column chromatography and 0.6 gof the desired product was obtained.

Example H18, Step 8

NaH (84 mg, 2.08 mmol) was added to the solution of 3-bromo-7,7-bis(hydroxymethyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11 (7H)-one (270mg, 0.796 mmol) in dry THF (50 mL) at 0° C. under nitrogen atmosphere.After 1 h, the solution of TsCl (106 mg, 0.557 mmol) in dry THF wasadded dropwise and stirred overnight at room temperature. The reactionmixture was quenched with aq NH₄Cl and extracted with DCM. The organiclayers were combined and dried over Na₂SO₄, filtered and concentrated togive the crude product. After purification with column chromatography,60 mg of the desired product was obtained. MS (ESI+): 321, 323 (M+H⁺).

Example H19. Synthesis of (R)-hexahydropyrrolo[1,2-a]pyrazin-3(4H)-one

Example H19, Step 1

To a solution of (R)-tert-butyl 2-(aminomethyl)pyrrolidine-1-carboxylate(5.0 g, 25 mmol) and DIPEA (1.6 g, 12.4 mmol) in CH₂Cl₂ (30 mL) wasadded 2-chloroacetyl chloride (3.0 g, 26.5 mmol) in CH₂Cl (10 mL) at 0°C. The mixture was stirred at room temperature overnight. Then thereaction mixture was poured into H₂O (30 mL) and extracted with CH₂Cl₂(3×50 mL). The combined organic layers were washed with brine, driedover Na₂SO₄. After filtration and concentration, the crude product waspurified by column chromatography (EtOAc:n-hexane=1:1) to give thedesired product (5.6 g).

Example H19, Step 2

To a solution of (R)-tert-butyl2-((2-chloroacetamido)methyl)pyrrolidine-1-carboxylate (5.6 g, 20.2mmol) in H₂O (20 mL) and acetone (20 mL) was added trifluoroacetic acid(10 mL). The reaction mixture was stirred at room temperature overnightand adjusted pH to 7 with 10% NaOH. To the aqueous solution was addedK₂CO₃ (2.0 g) and a catalytic amount of KI. The mixture was heated atreflux for 3 h. The reaction was cooled to room temperature, then themixture was extracted with CH₂Cl₂ (3×50 mL). The combined organic layerswere washed with brine, dried over Na₂SO₄ and concentrated under reducedpressure to give the crude product (1.7 g), which was directly used forthe next step without further purification.

mGluR5 PAM EC₅₀ values: +++++<10 nM; ++++ is between 10 and 30 nM; +++is between 30 and 100 nM; ++ is between 100 and 300 nM; + is between 300and 1,000 nM. Fold shift at 10 μM: +++>3; ++ is between 2.0 and 2.9; +is between 1.5 and 1.9. Fold shift at 1 μM: +++>3; ++ is between 2.0 and2.9; + is between 1.5 and 1.9.

Compound Synthesis Method & Data

See PCT/US2010/061147.

Synthesized from methyl 5-oxopyrrolidine-3- carboxylate,2-amino-4-bromobenzoic acid, and 2- ethynylpyridine according to GeneralExperimentals B1, G6 and A1. MS (ESI+): m/z 346 (M + H⁺); ¹H NMR (300MHz, CD₃OD) δ 8.89-8.79 (brs, 1H), 8.55-8.50 (t, J = 7.82 Hz, 1H),8.41-8.38 (d, J = 8.28 Hz, 1H), 8.24- 8.21 (d, J = 7.83 Hz, 1H),8.01-7.97 (m, 2H), 7.93-7.90 (d, J = 8.25 Hz, 1H), 4.46-4.39 (dd, J =12.00, 8.70 Hz, 1H), 4.23-4.16 (dd, J = 12.00, 8.40 Hz, 1H), 3.56-3.36(m, 2H), 2.92-2.86 (t, J = 8.70 Hz, 1H), 1.32 (s, 6H).

Synthesized from methyl 5-oxopyrrolidine-3- carboxylate,2-amino-4-bromobenzoic acid, and 2- ethynylpyridine according to GeneralExperimentals B1, G6, E1, and A1. MS (ESI+): m/z 348 (M + H⁺); ¹H NMR(300 MHz, CD₃OD) δ 8.89-8.88 (d, J = 5.37 Hz, 1H), 8.60-8.55 (t, J =7.96 Hz, 1H), 8.40-8.37 (d, J = 8.28 Hz, 1H), 8.27-8.25 (d, J = 7.95 Hz,1H), 8.05-8.03 (m, 1H), 8.01 (s, 1H), 7.90-7.87 (d, J = 8.19 Hz, 1H),4.53-4.47 (dd, J = 12.00, 9.00 Hz, 1H), 4.19-4.12 (dd, J = 12.30, 8.70Hz, 1H), 3.46-3.43 (m, 2H), 3.12-3.01 (m, 1H), 1.53-1.46 (d, J = 21.19Hz, 6H).

Synthesized from methyl 5-oxopyrrolidine-3- carboxylate,2-amino-4-bromobenzoic acid, and 2- ethynylpyridine according to GeneralExperimentals B1, G6, G13, and A1. MS (ESI+): m/z 360 (M + H⁺); ¹H NMR(300 MHz, CD₃OD) δ 8.87-8.85 (d, J = 5.67 Hz, 1H), 8.52-8.47 (t, J =7.94 Hz, 1H), 8.39-8.37 (d, J = 8.28 Hz, 1H), 8.21-8.18 (d, J = 8.25 Hz,1H), 7.97-7.94 (m, 2H), 7.91-7.88 (d, J = 8.37 Hz, 1H), 4.42-4.35 (m,1H), 4.25-4.18 (m, 1H), 3.56-3.48 (m, 2H), 3.39 (s, 3H), 3.01-2.92 (m,1H), 1.30 (s, 6H). mGluR5 PAM EC₅₀: ++++. Fold shift at 1 μM: +++.

Synthesized from 3-methoxypropan-1-ol, 2-amino-4- bromobenzoic acid, and2-ethynylpyridine according to General Experimentals G15, C1, B1, andA1. MS (ESI+): m/z 346 (M + H⁺); ¹H NMR (300 MHz, MeOD): δ 8.67 (d, J =4.4 Hz, 1H), 8.27 (d, J = 8.2 Hz, 1H), 7.87 (s, 1H), 7.76-7.71 (m, 1H),7.65-7.58 (m, 2H), 7.33-7.30 (m, 1H), 4.45-4.39 (m, 1H), 3.85-3.78 (m,1H), 3.53- 3.49 (t, J = 5.9 Hz, 1H), 3.35 (s, 3H), 3.32-3.27 (m, 1H),2.97-2.88 (m, 1H), 2.83-2.73 (m, 1H), 1.90-1.84 (m, 2H). mGluR5 PAMEC₅₀: ++.

Synthesized from oxetan-3-one, 2-amino-4- bromobenzoic acid, and2-ethynylpyridine according to General Experimentals C1, B1, and A1. MS(ESI+): m/z 330 (M + H)⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.60 (d, J = 5.1Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H), 7.96-7.90 (m, 1H), 7.85 (s, 1H),7.75-7.68 (m, 2H), 7.50-7.46 (s, 1H), 4.80 (s, 4H), 4.50 (s, 2H), 3.60(s, 2H). mGluR5 PAM EC₅₀: +++.

Synthesized from cyclobutanone, 2-amino-4- bromobenzoic acid, and2-ethynylpyridine according to General Experimentals C1, B1, and A1. MS(ESI+): m/z 328 (M + H⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.97 (d, J = 5.7 Hz,1H), 8.72-8.66 (m, 1H), 8.45 (d, J = 8.3 Hz, 1H), 8.36 (d, J = 8.0 Hz,1H), 8.16-8.11 (m, 2H), 8.04- 8.00 (dd, J = 8.3, 1.4 Hz, 1H), 4.41 (s,2H), 3.70 (s, 2H), 2.35-2.30 (m, 4H), 2.11-2.01 (m, 2H). mGluR5 PAMEC₅₀: ++++. Fold shift at 1 μM: +++.

Synthesized from 4-(trifluoromethyl)pyrrolidin-2-one, 2-amino-4-bromobenzoic acid and 2-ethynylpyridine according to GeneralExperimentals C1, B1 and A1. MS (ESI+): m/z 356 (M + H⁺); ¹H NMR (300MHz, CD₃OD): δ 8.94 (d, J = 5.4 Hz, 1H), 8.72-8.66 (m, 1H), 8.39-8.34(m, 2H), 8.15-8.10 (m, 1H), 8.05 (s, 1H), 7.90-7.87 (dd, J = 8.2, 1.2Hz, 1H), 4.58-4.51 (m, 1H), 4.41-4.35 (m, 1H), 3.77-3.66 (m, 2H),3.55-3.47 (m, 1H).

Synthesized from 2-fluoroacetaldehyde, 2-amino-4- bromobenzoic acid, and2-ethynylpyridine according to General Experimentals C1, B1 and A1. MS(ESI+): m/z 320 (M + H⁺); ¹H NMR (300 MHz, CD₃OD): δ 8.93 (d, J = 5.1Hz, 1H), 8.69-8.63 (m, 1H), 8.44-8.41 (d, J = 8.3 Hz, 1H), 8.33 (d, J =8.0 Hz, 1H), 8.13-8.07 (m, 2H), 7.98-7.95 (dd, J = 8.3, 1.3 Hz, 1H),4.74-4.56 (dd, J = 48.0, 5.1 Hz, 2H), 4.54-4.47 (m, 1H), 4.25-4.19 (m,1H), 3.75-3.66 (m, 1H), 3.47-3.33 (m, 2H).

Synthesized from butan-2-one, 2-amino-4-bromobenzoic acid, and2-ethynylpyridine according to General Experimentals C1, B1 and A1. MS(ESI+): m/z 330 (M + H⁺); ¹H NMR (300 MHz, CD₃OD): δ 8.96 (d, J = 5.8Hz, 1H), 8.72-8.67 (m, 1H), 8.45 (d, J = 8.3 Hz, 1H), 8.37 (d, J = 8.0Hz, 1H), 8.16-8.12 (m, 2H), 8.04-8.01 (d, J = 8.3 Hz, 1H), 4.13 (s, 2H),3.37 (s, 2H), 1.79-1.71 (q, J = 7.5 Hz, 2H), 1.34 (s, 3H), 1.07-1.02 (t,J = 7.5 Hz, 3H). mGluR5 PAM EC₅₀: ++++. Fold shift at 1 μM: +++.

Synthesized from 4,4-dimethylpyrrolidin-2-one, 2- amino-4-bromobenzoicacid, and 2-ethynylpyridine according to General Experimentals B1, E3,and A1. MS (ESI+): m/z 334 (M + H⁺); ¹H NMR (300 MHz, CD₃OD): δ 8.93 (d,J = 5.8 Hz, 1H), 8.71-8.66 (m, 1H), 8.40-8.34 (m, 2H), 8.13-8.09 (m,2H), 7.88 (d, J = 7.0 Hz, 1H), 5.49 (d, J = 53.1 Hz, 1H), 4.08-4.04 (m,1H), 3.95-3.91 (m, 1H), 1.43-1.27 (m, 6H).

Synthesized from methyl 5-oxopyrrolidine-3- carboxylate,2-amino-4-bromobenzoic acid, and 2- ethynylpyridine according to GeneralExperimentals B1, G3, G4, and A1. MS (ESI+): m/z 313 (M + H⁺); ¹H NMR(300 MHz, DMSO-d₆) δ 8.68-8.67 (d, J = 4.32 Hz, 1H), 8.19-8.17 (d, J =8.16 Hz, 1H), 7.98-7.93 (t, J = 7.41 Hz, 1H), 7.86 (s, 1H), 7.80-7.77(d, J = 7.65 Hz, 1H), 7.71-7.68 (dd, J = 8.15, 1.31 Hz, 1H), 7.53-7.50(t, J = 5.25 Hz, 1H), 4.51-4.45 (m, 1H), 4.27-4.21 (m, 1H), 3.96-3.91(t, J = 7.80 Hz, 1H), 3.60-3.46 (m, 2H).

Synthesized from ethyl 4-bromo-2-(2-ethoxy-2- oxoethyl)benzoate,4-methylpyrrolidin-2-one and 2- ethynylpyridine accoding to GeneralExperimentals B4, B2, and A1. MS (ESI+): m/z 301 (M + H⁺); ¹H NMR (300MHz, CD₃OD) δ 8.92 (d, J = 6.0 Hz, 1H), 8.69- 8.66 (m, 1H), 8.38-8.30(m, 2H), 8.14-8.09 (m, 1H), 8.02 (s, 1H), 7.74-7.70 (dd, J = 8.4, 1.2Hz, 1H), 6.70 (s, 1H), 4.39-4.32 (m, 1H), 3.78-3.71 (m, 1H), 3.36-3.32(m, 1H), 3.30-2.71 (m, 2H), 1.21 (d, J = 8.7 Hz, 3H).

Synthesized from ethyl 3-methylbut-2-enoate, 2-amino- 4-bromobenzoicacid, and 2-ethynylpyridine according to General Experimentals C3, B1,and A1. MS (ESI+): m/z 318 (M + H⁺); ¹H NMR (300 MHz, CD₃OD): δ 8.94-8.92 (d, J = 5.91 Hz, 1H), 8.73-8.67 (td, J = 7.97 Hz, 1.50 Hz, 1H),8.38-8.34 (m, 2H), 8.15-8.09 (m, 2H), 7.86-7.83 (d, J = 6.37 Hz, 1H),3.54 (s, 2H), 1.64 (s, 6H). mGluR5 PAM EC₅₀: +++. Fold shift at 1 μM: +.

Synthesized from 3,3-dimethylcyclopentanone, 3- bromo-2-fluoroaniline,and 2-ethynylpyridine according to General Experimentals D1, B1, and A1.MS (ESI+): m/z 334 (M + H⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.95- 8.93 (d, J= 5.88 Hz, 1H), 8.72-8.66 (td, J = 7.99, 1.49 Hz, 1H), 8.37-8.35 (d, J =8.01 Hz, 1H), 8.17-8.11 (m, 2H), 7.86-7.81 (m, 1H), 4.02 (s, 2H), 3.16(s, 2H), 1.33 (s, 6H). mGluR5 PAM EC₅₀: +++++.

Synthesized from 4-(trifluoromethyl)pyrrolidin-2-one, 3-amino-5-bromopicolinic acid, and 2-ethynylpyridine according to GeneralExperimentals C1, B1, and A1. MS (ESI+): m/z 357 (M + H⁺); ¹H NMR (300MHz, CD₃OD): δ 9.04 (d, J = 1.7 Hz, 1H), 8.98 (d, J = 5.9 Hz, 1H),8.75-8.69 (m, 1H), 8.46 (d, J = 1.8 Hz, 1H), 8.40 (d, J = 8.0 Hz, 1H),8.18-8.13 (m, 1H), 4.60-4.52 (m, 1H), 4.42-4.36 (m, 1H), 3.77-3.59 (m,2H), 3.67-3.38 (m, 1H). mGluR5 PAM EC₅₀: ++.

Synthesized from 3-methoxypropan-1-ol, 3-amino-5- bromopicolinic acid,and 2-ethynylpyridine according to General Experimentals G15, C1, B1,and A1. MS (ESI+): m/z 347 (M + H⁺); ¹H NMR (300 MHz, CD₃OD): 8.98 (d, J= 1.8 Hz, 1H), δ 8.70 (d, J = 4.8 Hz, 1H), 8.16 (d, J = 1.8 Hz, 1H),7.80-7.84 (m, 1H), 7.65-7.63 (m, 1H), 7.37-7.33 (m, 1H), 4.56-4.49 (m,1H), 3.94-3.85 (m, 1H), 3.53-3.49 (t, J = 5.9 Hz, 2H), 3.37 (s, 3H),3.32- 3.29 (m, 1H), 3.01-2.92 (m, 1H), 2.88-2.78 (m, 1H), 1.92-1.88 (m,2H). mGluR5 PAM EC₅₀: +.

Synthesized from butan-2-one, 3-amino-5- bromopicolinic acid, and2-ethynylpyridine according to General Experimentals C1, B1, and A1. MS(ESI+): m/z 331 (M + H⁺); ¹H NMR (300 MHz, CD₃OD): δ 9.01 (s, 1H), 8.94(d, J = 5.8 Hz, 1H), 8.65 (m, 1H), 8.41 (s, 1H), 8.34 (d, J = 7.9 Hz,1H), 8.12-8.07 (m, 1H), 4.03 (s, 2H), 3.20-2.99 (m, 2H), 1.73-1.66 (q, J= 7.5 Hz, 2H), 1.27 (s, 3H), 1.04-0.99 (t, J = 7.5 Hz, 3H). mGluR5 PAMEC₅₀: +++. Fold shift at 1 μM: ++.

Synthesized from 3,3-dimethylcyclopentanone, 3-amino- 5-bromopicolinicacid, and 2-ethynylpyridine according to General Experimentals B1, E3,and A1. MS (ESI+): m/z 335 (M + H⁺); ¹H NMR (300 MHz, CD₃OD): δ 9.05 (s,1H), 8.95 (d, 1H), 8.70-8.67 (m, 1H), 8.64 (s, 1H), 8.54-8.37 (m, 1H),8.14-8.09 (m, 1H), 5.49 (d, J = 52.5 Hz, 1H), 4.13-3.95 (m, 2H), 1.35(s, 6H). mGluR5 PAM EC₅₀: ++.

Synthesized from (R)-pyrrolidin-2-ylmethanamine, 2- amino-4-bromobenzoicacid and 2-ethynylpyridine according to General Experimentals H15, B1,and A1. MS (ESI+): m/z 329 (M + H⁺); 1H NMR (300 MHz, CD₃OD): δ 8.88 (d,J = 5.1 Hz, 1H), 8.55-8.51 (t, J = 4.8 Hz, 1H), 8.28 (d, J = 8.1 Hz,1H), 8.23 (d, J = 8.1 Hz, 1H), 8.03-8.01 (m, 1H), 7.99 (s, 1H),7.81-7.77 (dd, J = 8.1, 1.5 Hz, 1H), 4.55-4.46 (m, 2H), 4.22-4.19 (m,1H), 3.77-3.73 (m, 2H), 2.36-2.29 (m, 3H), 1.82-1.78 (m, 1H). mGluR5 PAMEC₅₀: +++. Fold shift at 1 μM: +++.

Synthesized from (S)-pyrrolidin-2-ylmethanamine, 2- amino-4-bromobenzoicacid and 2-ethynylpyridine according to General Experimentals H15, B1,and A1. MS (ESI+): m/z 329 (M + H⁺). mGluR5 PAM EC₅₀ : ++.

Synthesized from piperidin-2-ylmethanamine, 2-amino- 4-bromobenzoic acidand 2-ethynylpyridine according to General Experimentals H15, B1, andA1. MS (ESI): 343 (MH⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.92-8.91 (d, J = 4.8Hz, 1H), 8.65-8.59 (m, 1H), 8.31-8.26 (m, 2H), 8.10- 8.05 (m, 1H), 7.94(s, 1H), 7.80-7.76 (dd, J = 1.5 Hz, 8.4 Hz, 1H), 4.56-4.53 (m, 1H),4.40-4.20 (m, 2H), 3.95- 3.89 (m, 1H), 3.55-3.40 (m, 1H), 2.20-2.10 (m,1H), 2.10-1.90 (m, 2H), 1.80-1.70 (m, 3H). mGluR5 PAM EC₅₀: +++.

See PCT/US2010/061147.

See PCT/US2010/061147.

See PCT/US2010/061147.

See PCT/US2010/061147.

See PCT/US2010/061147.

See PCT/US2010/061147.

See PCT/US2010/061147.

See PCT/US2010/061147.

See PCT/US2010/061147.

See PCT/US2010/061147.

See PCT/US2010/061147.

See PCT/US2010/061147.

Synthesized from 5-hydroxypiperidin-2-one, 2-amino-4- bromobenzoic acid,and 2-ethynylpyridine according to General Experimentals F1, B1, F4,G16, G8, E1 and A1. MS (ESI+): m/z 334 (M + H⁺); ¹H NMR (300 MHz, CD₃OD)δ 8.93-8.92 (d, J = 5.67 Hz, 1H), 8.64-8.59 (t, J = 7.95 Hz, 1H),8.46-8.44 (d, J = 8.28 Hz, 1H), 8.32- 8.29 (d, J = 8.07 Hz, 1H),8.09-8.00 (m, 3H), 4.70-4.69 (t, J = 15.09 Hz, 1H), 3.98-3.81 (q, 1H),3.49-3.40 (m, 2H), 2.46-2.37 (m, 1H), 2.31-2.13 (m, 1H), 1.73-1.67 (d, J= 20.96 Hz, 3H).

Synthesized from 5-(trifluoromethyl)piperidin-2-one, 2-amino-4-bromobenzoic acid, and 2-ethynylpyridine according to GeneralExperimentals B1 and A1. MS (ESI): 370 (M + H+); ¹H NMR (300 MHz, CD₃OD)δ 8.92-8.90 (d, J = 5.6 Hz, 1H), 8.61-8.56 (td, J = 8.0, 1.5 Hz, 1H),8.45-8.43 (d, J = 8.3 Hz, 1H), 8.29-8.27 (d, J = 8.0 Hz, 1H), 8.07-8.02(m, 2H), 7.99-7.96 (dd, J = 8.3, 1.3 Hz, 1H), 4.62-4.55 (dd, J = 14.2,5.7 Hz, 1H), 4.09- 4.01 (m, 1H), 3.40-3.36 (m, 2H), 3.21-3.09 (m, 1H),2.45-2.39 (m, 1H), 2.14-2.04 (m, 1H).

Synthesized from 3-methylcyclopentenone, 3-amino-5- bromopicolinic acid,and 2-ethynylpyridine according to General Experimentals G30, C2, B1, E3and A1. MS (ESI+): m/z 349 (M + H⁺); ¹H NMR (300 MHz, CD₃OD) δ 9.08 (s,1H), 8.98-8.96 (d, J = 5.82 Hz, 1H), 8.72-8.67 (td, J = 7.98, 1.86 Hz,1H), 8.54 (s, 1H), 8.40-8.37 (d, J = 7.92 Hz, 1H), 8.20-8.12 (t, J =7.05 Hz, 1H), 5.75-5.56 (dt, J = 48.00, 5.72 Hz, 1H), 4.10-3.95 (q, 2H),2.29-2.14 (m, 2H), 1.20 (s, 3H), 1.16 (s, 3H).

Synthesized from 3-methylcyclopentanone, 3-amino-5- bromopicolinic acid,and 2-ethynylpyridine according to General Experimentals C2, B1, and A1.MS (ESI+): m/z 317 (M + H⁺). and

Synthesized from 5-hydroxypiperidin-2-one, 2-amino-4- bromobenzoic acid,and 2-ethynylpyridine according to General Experimentals F1, B1, F4,G16, G8, and A1. MS (ESI+): m/z 344 (M + H⁺). mGluR5 PAM EC₅₀: +.

Synthesized from methyl 6-oxopiperidine-3-carboxylate,2-amino-4-bromobenzoic acid, and 2-ethynylpyridine according to GeneralExperimentals B1, G3, and A1. MS (ESI+): m/z 345 (M + H⁺); ¹H NMR (300MHz, CD₃OD) δ 8.61-8.59 (d, J = 4.71 Hz, 1H), 8.25-8.22 (d, J = 8.28 Hz,1H), 7.95-7.90 (td, J = 7.80, 1.50 Hz, 1H), 7.82 (s, 1H), 7.75-7.72 (d,J = 7.83 Hz, 1H), 7.68-7.65 (d, J = 8.13 Hz, 1H), 7.50-7.46 (m, 1H),4.41-4.34 (m, 1H), 4.17-4.10 (m, 1H), 3.18-2.98 (m, 3H), 2.28-2.11 (m,2H).

Synthesized from cyclopent-3-enecarboxylic acid, 2- amino-4-bromobenzoicacid, and 2-ethynylpyridine according to General Experimentals H1, B1,and A1. MS (ESI+): m/z 344 (M + H⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.95-8.93(d, J = 6.0 Hz, 1H), 8.71-8.65 (m, 1H), 8.39-8.33 (m, 2H), 8.14-8.11 (m,1H), 8.04 (s, 1H), 7.93-7.89 (dd, J = 8.1, 1.5 Hz, 1H), 5.27 (s, 1H),3.84- 3.81 (m, 1H), 3.64-3.63 (m, 1H), 3.51 (s, 3H), 2.31-2.15 (m, 3H),2.06-2.03 (m, 1H).

Synthesized from 4-(trifluoromethyl)piperidine, 3-amino-5-bromopicolinic acid, and 2-ethynylpyridine according to GeneralExperimentals F6, C4, F3, B1, and A1. MS (ESI+): m/z 371 (M + H⁺).mGluR5 PAM EC₅₀: +++.

The mixture of Example 2.22 and Example 2.23 were synthesized from3-ethylcyclopentanone, 3-amino-5- bromopicolinic acid, and2-ethynylpyridine according to General Experimentals C2, B1, and A1. MS(ESI+): m/z 331 (M + H⁺). mGluR5 PAM EC₅₀: ++. and

Synthesized from 3-methylcyclopentenone, 2-amino-4- bromobenzoic acid,and 6-bromopicolinonitrile according to General Experimentals G30, C2,B1, and A2. MS (ESI+): m/z 355 (M + H⁺); ¹H NMR (300 MHz, CD₃OD) δ8.41-8.38 (d, J = 8.28 Hz, 1H), 8.14-8.09 (t, J = 7.86 Hz, 1H),8.00-7.89 (m, 4H), 4.21-4.17 (t, J = 6.43 Hz, 2H), 3.07 (s, 2H),2.01-1.97 (t, J = 6.48 Hz, 2H), 1.22 (s, 6H). mGluR5 PAM EC₅₀: +++++.

Synthesized from 3-methylcyclopentenone, 2-amino-4- bromobenzoic acid,and 6-bromopicolinonitrile according to General Experimentals G30, C2,B1, and A2. MS (ESI+): m/z 348 (M + H⁺); ¹H NMR (300 MHz, CD₃OD) δ8.41-8.38 (d, J = 8.22 Hz, 1H), 8.14-8.09 (t, J = 7.83 Hz, 1H),8.00-7.91 (m, 4H), 3.88 (s, 2H), 3.37- 3.33 (m, 2H), 1.90-1.86 (t, J =6.68 Hz, 2H), 1.19 (s, 6H). mGluR5 PAM EC₅₀: ++++.

Synthesized from 3-methylcyclopentenone, 2-amino-4- bromobenzoic acid,and 2-ethynylisonicotinonitrile according to General Experimentals G30,C2, B1, and A1. MS (ESI+): m/z 355 (M + H⁺); ¹H NMR (300 MHz, CD₃OD) δ8.88-8.86 (d, J = 5.07 Hz, 1H), 8.41-8.39 (d, J = 8.28 Hz, 1H), 8.12 (s,1H), 7.95-7.92 (d, J = 8.31 Hz, 1H), 7.89 (s, 1H), 7.83-7.81 (d, J =5.10 Hz, 1H), 4.21- 4.17 (t, J = 6.48 Hz, 2H), 3.07 (s, 2H), 2.01-1.97(t, J = 6.48 Hz, 2H), 1.22 (s, 6H). mGluR5 PAM EC₅₀: ++++.

Synthesized from 3-methylcyclopentenone, 2-amino-4- bromobenzoic acid,and 2-ethynylisonicotinonitrile according to General Experimentals G30,C2, B1, and A1. MS (ESI+): m/z 355 (M + H⁺); ¹H NMR (300 MHz, CD₃OD) δ8.88-8.86 (d, J = 4.92 Hz, 1H), 8.41-8.38 (d, J = 8.31 Hz, 1H), 8.12 (s,1H), 7.94-7.92 (d, J = 8.34 Hz, 1H), 7.89 (s, 1H), 7.82-7.81 (d, J =3.87 Hz, 1H), 3.88 (s, 2H), 3.35-3.31 (m, 2H), 1.89-1.85 (t, J = 6.80Hz, 2H), 1.19 (s, 6H). mGluR5 PAM EC₅₀: +++++.

Synthesized from 1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidine-2-carboxylic acid, 2-amino-4- bromobenzoic acid, and2-ethynylpyridine according to General Experimentals G1, G17, G18, C5,B1, and A1. MS (ESI+): m/z 371 (M + H⁺); mGluR5 PAM EC₅₀: ++.

Synthesized from methyl 6-oxopiperidine-3-carboxylate,2-amino-4-bromobenzoic acid, and 2-ethynylpyridine according to GeneralExperimentals B1, G3, G4, and A1. MS (ESI+): m/z 327 (M + H⁺); ¹H NMR(300 MHz, DMSO-d₆) δ 8.67 (s, 1H), 8.20-8.17 (d, J = 7.83, 1H),7.98-7.93 (m, 1H), 7.85 (s, 1H), 7.80-7.69 (m, 2H), 7.54- 7.52 (m, 1H),4.32-4.19 (m, 2H), 3.68-3.66 (m, 1H), 3.08-3.04 (t, J = 6.36 Hz, 2H),2.34-2.27 (m, 1H), 2.15- 2.10 (m, 1H).

Synthesized from 5-hydroxypiperidin-2-one, 2-amino-4- bromobenzoic acid,and 2-ethynylpyridine according to General Experimentals F1, B1, F4,G16, G8, G14, and A1. MS (ESI+): m/z 314 (M + H⁺); ¹H NMR (300 MHz,CD₃OD) δ 8.88-8.86 (d, J = 5.55 Hz, 1H), 8.55-8.50 (t, J = 7.88 Hz, 1H),8.41-8.38 (d, J = 8.28 Hz, 1H), 8.24-8.21 (d, J = 7.98 Hz, 1H),8.00-7.97 (m, 2H), 7.91-7.88 (d, J = 8.22 Hz, 1H), 7.38 (s, 1H),3.29-3.26 (m, 2H), 2.55- 2.50 (t, J = 7.92 Hz, 2H), 2.01 (s, 3H).

Synthesized from ethyl 2-amino-4-bromobenzoate, 2- amino-4-bromobenzoicacid, and 2-ethynylpyridine according to General Experimentals B3 andA1. MS (ESI+): m/z 332 (M + H⁺); ¹H NMR (300 MHz, CD₃OD): δ 8.95 (d, J =5.8 Hz, 1H), 8.71-8.66 (m, 1H), 8.39-8.34 (m, 2H), 8.15-8.10 (m, 1H),7.92-7.89 (m, 2H), 4.58 (s, 2H), 3.93 (s, 2H), 1.27 (s, 6H). mGluR5 PAMEC₅₀: ++++. Fold shift at 1 μM: +++.

Synthesized from 3-methylcyclopentenone, 3-bromo-2- fluoroaniline, and2-ethynylpyridine according to General Experimentals G30, C2, D1, B1,and A1. Mixture of Example 2.30a and Example 2.30b: MS (ESI+): m/z 348(M + H⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.62-8.61 (d, J = 4.74 Hz, 1H),8.03-8.00 (d, J = 8.34 Hz, 1H), 7.96-7.91 (td, J = 7.77, 1.64 Hz, 1H),7.76-7.74 (d, J = 7.86 Hz, 1H), 7.66-7.61 (m, 1H), 7.52-7.47 (m, 1H),4.13-4.08 (t, J = 6.57 Hz, 0.5H), 3.85 (s, 1.5H), 3.11-3.07 (t, J = 7.08Hz, 1.5H), 2.86 (s, 0.5H), 1.92- 1.89 (t, J = 6.54 Hz, 0.5H), 1.82-1.77(t, J = 7.08 Hz, 1.5H), 1.15 (s, 1.5H), 1.12 (s, 4.5H). Example 2.30a:mGluR5 PAM EC₅₀: ++++. Example 2.30b: mGluR5 PAM EC₅₀: +++++. Fold shiftat 1 μM: +++. and

Synthesized from 3-methylcyclopentenone, 3-bromo-4- fluoroaniline, and2-ethynylpyridine according to General Experimentals G30, C2, D1, B1,and A1. MS (ESI+): m/z 348 (M + H⁺); ¹H NMR (300 MHz, DMSO- d₆) δ 8.71(brs, 1H), 7.98-7.91 (m, 3H), 7.79-7.77 (m, 1H), 7.51-7.49 (m, 1H),3.99-3.95 (t, J = 6.45 Hz, 2H), 2.79 (s, 2H), 1.81-1.76 (t, J = 6.45 Hz,2H), 1.05 (s, 6H). mGluR5 PAM EC₅₀: +++.

Synthesized from 3-methylcyclopentenone, 3-bromo-4- fluoroaniline, and2-ethynylpyridine according to General Experimentals G30, C2, D1, B1,and A1. MS (ESI+): m/z 348 (M + H⁺); ¹H NMR (300 MHz, DMSO- d₆) δ8.68-8.67 (d, J = 4.80 Hz, 1H), 7.98-7.91 (m, 3H), 7.79-7.60 (m, 1H),7.54-7.51 (m, 1H), 3.74 (s, 2H), 3.02- 2.97 (t, J = 7.02 Hz, 2H),1.70-1.65 (t, J = 6.99 Hz, 2H), 1.03 (s, 6H).

Synthesized from 3-methylcyclopentenone, 3-bromo-5- fluoroaniline, and2-ethynylpyridine according to General Experimentals G30, C2, D1, B1,and A1. MS (ESI+): m/z 364 (M + H⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.93-8.92(d, J = 5.67 Hz, 1H), 8.66-8.61 (td, J = 7.93, 1.50 Hz, 1H), 8.34-8.31(d, J = 7.98 Hz, 1H), 8.10-8.06 (td, J = 5.85, 1.08 Hz, 1H), 7.93-7.89(dd, J = 8.73, 2.40 Hz, 1H), 7.61-7.58 (dd, J = 8.43, 2.40 Hz, 1 H),4.20- 4.16 (t, J = 6.42 Hz, 2H), 3.07 (s, 2H), 2.02-1.98 (t, J = 6.42Hz, 2H), 1.22 (s, 6H).

Synthesized from 3-methylcyclopentenone, 3-bromo-5- fluoroaniline, and2-ethynylpyridine according to General Experimentals G30, C2, D1, B1,E3, and A1. MS (ESI+): m/z 366 (M + H⁺); ¹H NMR (300 MHz, CD₃OD) δ8.92-8.90 (d, J = 5.46 Hz, 1H), 8.69-8.64 (t, J = 7.92 Hz, 1H),8.37-8.35 (d, J = 8.04 Hz, 1H), 8.11- 8.06 (t, J = 6.33 Hz, 1H),7.82-7.78 (dd, J = 8.64, 2.55, 1H), 7.67-7.63 (dd, J = 9.24, 2.46 Hz,1H), 5.71-5.51 (dt, J = 47.70, 5.52 Hz, 1H), 4.02-3.92 (q, 2H),2.26-2.21 (m, 1H), 2.17-2.13 (t, J = 5.10 Hz, 1H), 1.20 (s, 3H), 1.13(s, 3H).

Synthesized from 3-methylcyclopentenone, 3-bromo-5- chloroaniline, and2-ethynylpyridine according to General Experimentals G30, C2, D1, B1,and A1. MS (ESI+): m/z 364 (M + H⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.90-8.89(d, J = 5.73 Hz, 1H), 8.59-8.55 (td, J = 8.66, 1.41 Hz, 1H), 8.30-8.28(d, J = 7.98 Hz, 1H), 8.05-8.01 (m, 2H), 7.81 (s, 1H), 4.18-4.14 (t, J =6.45 Hz, 2H), 3.00 (s, 2H), 2.00-1.95 (t, J = 6.43 Hz, 2H), 1.20 (s,6H).

Synthesized from 3-methylcyclopentenone, 3-bromo-4- methylaniline, and2-ethynylpyridine according to General Experimentals G30, C2, D1, B1,and A1. MS (ESI+): m/z 344 (M + H⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.86-8.84(d, J = 5.70 Hz, 1H), 8.48-8.43 (td, J = 7.77, 1.43 Hz, 1H), 8.25 (s,1H), 8.19-8.17 (d, J = 7.89 Hz, 1H), 8.10 (s, 1H), 7.94-7.90 (m, 1H),4.20-4.15 (t, J = 6.56 Hz, 2H), 3.09 (s, 2H), 2.57 (s, 3H), 1.98-1.94(t, J = 6.62 Hz, 2H), 1.20 (s, 5H).

Synthesized from 3-methylcyclopentenone, 3-bromo-4- methylaniline, and2-ethynylpyridine according to General Experimentals G30, C2, D1, B1,and A1. MS (ESI+): m/z 344 (M + H⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.91-8.89(d, J = 6.21 Hz, 1H), 8.57-8.51 (td, J = 7.97, 1.50 Hz, 1H), 8.28-8.24(m, 2H), 8.16 (s, 1H), 8.02-7.97 (t, J = 6.75 Hz, 1H), 3.91 (s, 2H),3.44-3.39 (t, J = 6.87 Hz, 2H), 2.58 (s, 3H), 1.89-1.84 (t, J = 6.89 Hz,2H), 1.17 (s, 6H).

Synthesized from pyrrolidine-2-carboxylic acid, 2-amino-6-bromonicotinic acid, and 2-ethynylpyridine according to GeneralExperimentals F5, G1, G9, G17, G18, C5, B1, and A1. MS (ESI+): m/z 358(M + H⁺).

Synthesized from pyrrolidine-2-carboxylic acid, 3-amino-5-bromopicolinic acid, and 2-ethynylpyridine according to GeneralExperimentals F5, G1, G9, G17, G18, C5, B1, and A1. MS (ESI+): m/z 358(M + H⁺).

Synthesized from 3-methylcyclopentenone, 2-amino-4- bromobenzoic acid,and ethynylbenzene according to General Experimentals G30, C2, B1, andA1. MS (ESI+): m/z 329 (M + H⁺). mGluR5 PAM EC₅₀: +++++. Fold shift at 1μM: ++.

Synthesized from 5-hydroxypiperidin-2-one, 2-amino-4- bromobenzoic acid,and 2-ethynylpyridine according to General Experimentals F1, B1, F4,G16, G8, E1 and A1. MS (ESI+): m/z 346 (M + H⁺). mGluR5 PAM EC₅₀: ++++.

Synthesized form isobutyronitrile, 2-amino-4- bromobenzoic acid,ethynyltrimethylsilane, and 6- bromonicotinonitrile according to GeneralExperimentals C6, B1, and A2. MS (ESI+): 355 (M + H⁺); ¹H NMR (300 MHz,CDCl₃): δ 8.92 (s, 1H), 8.29 (d, J = 8.2 Hz, 1H), 8.02-7.98 (dd, J =8.2, 2.0 Hz, 1H), 7.86 (s, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.61 (d, J =8.3 Hz, 1H), 3.84 (s, 2H), 3.07-3.02 (t, J = 7.1 Hz, 2H), 1.80-1.75 (t,J = 7.0 Hz, 2H), 1.13 (s, 6H). mGluR5 PAM EC₅₀: ++++.

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid,ethynyltrimethylsilane, and 2- bromo-5-methoxypyridine according toGeneral Experimentals C6, B1, and A2, MS (ESI+): 360 (M + H⁺); ¹H NMR(300 MHz, CDCl₃) δ 8.36 (s, 1H), 8.24 (d, J = 8.2 Hz, 1H), 7.81 (s, 1H),7.61-7.53 (m, 2H), 7.24-7.20 (dd, J = 8.6, 2.7 Hz, 1H), 3.92 (s, 3H),3.82 (s, 2H), 3.06-3.02 (t, J = 7.1 Hz, 2H), 1.79-1.74 (t, J = 7.1 Hz,2H), 1.12 (s, 6H). mGluR5 PAM EC₅₀: +++.

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid, and2-ethynyl-6-methylpyridine according to General Experimentals C6, B1,and A1. MS (ESI+): 344 (M + H⁺); ¹H NMR (300 MHz, CDCl₃): δ 8.24 (d, J =8.3 Hz, 1H), 7.84 (s, 1H), 7.64-7.59 (m, 2H), 7.42 (d, J = 7.7 Hz, 1H),7.17 (d, J = 7.7 Hz, 1H), 3.83 (s, 2H), 3.06-3.01 (t ,J = 7.1 Hz, 2H),2.62 (s, 3H), 1.79-1.74 (t, J = 7.1 Hz, 2H), 1.12 (s, 6H). mGluR5 PAMEC₅₀: ++++. Fold shift at 1 μM: +++.

Synthesized from isobutyronitrile, 2-amino-4- bormobenzoic acid,ethynyltrimethylsilane, and 2- bromo-5-chloropyridine according toGeneral Experimentals C6, B1, and A2. MS (ESI+): 364 (M + H⁺); ¹H NMR(300 MHz, CDCl₃) δ 8.62 (s, 1H), 8.27 (d, J= 8.2 Hz, 1H), 7.83 (s, 1H),7.73-7.70 (dd, j = 8.3, 2.9 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.54 (d,J = 8.2 Hz, 1H), 3.84 (s, 2H), 3.06-3.02 (t, J = 7.1 Hz, 2H), 1.79-1.74(t, J = 7.0 Hz, 2H), 1.12 (s, 6H). mGluR5 PAM EC₅₀: +++++. Fold shift at1 μM: +++.

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid,ethynyltrimethylsilane, and 2- bromo-5-fluoropyridine according toGeneral Experimentals C6, B1, and A2. MS (ESI+): 348 (M + H⁺); ¹H NMR(300 MHz, CDCl₃) δ 8.52 (d, J = 2.8 Hz, 1H), 8.26 (d, J = 8.2 Hz, 1H),7.83 (s, 1H), 7.63-7.59 (m, 2H), 7.50-7.43 (dd, J = 9.2, 2.9 Hz, 1H),3.84 (s, 2H), 3.06-3.02 (t, J = 7.1 Hz, 2H), 1.79-1.75 (t, J = 7.1 Hz,2H), 1.12 (s, 6H). mGluR5 PAM EC₅₀: +++++. Fold shift at 1 μM: ++.

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid, and1-ethynyl-3-methylbenzene according to General Experimentals C6, B1, andA1. MS (ESI+): 343 (M + H⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.23 (d, J = 8.3Hz, 1H), 7.76 (s, 1H), 7.56-7.53 (m, 1H), 7.40 (d, J = 9.7 Hz, 2H),7.31-7.30 (m, 1H), 7.20 (d, J = 7.6 Hz, 1H), 3.84 (s, 2H), 3.06-3.02 (t,J = 7.1 Hz, 2H), 2.39 (s, 3H), 1.79-1.74 (t, J = 7.1 Hz, 2H), 1.12 (s,6H). mGluR5 PAM EC₅₀: +++++. Fold shift at 1 μM: +++.

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid,ethynyltrimethylsilane, and 3- bromobenzonitrile according to GeneralExperimentals C6, B1, and A2. MS (ESI+): 354 (M + H⁺); ¹H NMR (300 MHz,CDCl₃): δ 8.28 (d, J = 8.2 Hz, 1H), 7.87 (s, 1H), 7.81-7.78 (m, 2H),7.68-7.65 (m, 1H), 7.56-7.49 (m, 2H), 3.84 (s, 2H), 3.07-3.02 (t, J =7.1 Hz, 2H), 1.84- 1.75 (t, J = 7.1 Hz, 2H), 1.13 (s, 6H). mGluR5 PAMEC₅₀: ++++. Fold shift at 1 μM: ++.

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid,ethynyltrimethylsilane, and 4- bromo-2-methylpyridine according toGeneral Experimentals C6, B1, and A2. MS (ESI+): 344 (M + H⁺); ¹H NMR(300 MHz, CDCl₃) δ 8.54-8.53 (d, J = 5.04 Hz, 1H), 8.28-8.25 (d, J =8.25 Hz, 1H), 7.79 (s, 1H), 7.57-7.54 (dd, J = 7.95, 1.50 Hz, 1H), 7.32(s, 1H), 7.26-7.24 (d, J = 4.95 Hz, 1H), 3.84 (s, 2H), 3.07-3.02 (t, J =7.11 Hz, 2H), 2.60 (s, 3H), 1.80-1.75 (t, J = 7.08 Hz, 2H), 1.13 (s,6H). mGluR5 PAM EC₅₀: ++++.

Synthesized from isobutyonitrile, 2-amino-4- bromobenzoic acid,ethynyltrimethylsilane, and 2- bromo-4-methylthiazole according toGeneral Experimentals C6, B1, and A2. MS (ESI+): 350 (M + H⁺); ¹H NMR(300 MHz, CDCl₃) δ 8.27 (d, J = 8.3 Hz, 1H), 7.82 (s, 1H), 7.59 (d, J =8.2 Hz, 1H), 7.01 (s, 1H), 3.83 (s, 2H), 3.06-3.01 (t, J = 7.1 Hz, 2H),2.53 (s, 3H), 1.79-1.75 (t, J = 7.1 Hz, 2H), 1.12 (s, 6H).

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid,ethynyltrimethylsilane, and 5- bromo-2-methylthiazole according toGeneral Experimentals C6, B1, and A2. MS (ESI+): 350 (M + H⁺); ¹H NMR(300 MHz, CDCl₃): δ 8.24 (d, J = 8.1 Hz, 1H), 7.86 (s, 1H), 7.74 (s,1H), 7.53-7.50 (dd, J = 8.2, 1.4 Hz, 1H), 3.84 (s, 2H), 3.06-3.01 (t, J= 7.1 Hz, 2H), 2.75 (s, 3H), 1.79-1.75 (t, J = 7.0 Hz, 2H), 1.13 (s,6H). mGluR5 PAM EC50: +++++. Fold shift at 1 μM: ++.

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid,ethynyltrimethylsilane, and 2- bromo-5-methylthiazole according toGeneral Experimentals C6, B1, and A2. MS (ESI+): 350 (M + H⁺); ¹H NMR(300 MHz, CDCl₃) δ 8.27 (d, J = 8.3 Hz, 1H), 7.81 (s, 1H), 7.60-7.56 (m,2H), 3.83 (s, 2H), 3.06-3.01 (t, J = 7.1 Hz, 2H), 2.55 (s, 3H),1.79-1.75 (t, J = 7.1 Hz, 2H), 1.12 (s, 6H). mGluR5 PAM EC₅₀: +++++.

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid,ethynyltrimethylsilane, and 5- bromo-3-methylisothiazole according toGeneral Experimentals C6, B1, and A2. MS (ESI+): 350 (M + H⁺); ¹H NMR(300 MHz, CDCl₃) δ 8.28-8.25 (d, J = 8.25 Hz, 1H), 7.77-7.60 (d, J =1.14 Hz, 1H), 7.55-7.52 (dd, J = 8.25, 1.47 Hz, 1H), 7.20 (s, 1H), 3.84(s, 2H), 3.07-3.02 (t, J = 7.11 Hz, 2H), 2.54 (s, 3H), 1.80-1.75 (t, J =7.16 Hz, 2H), 1.13 (s, 6H). mGluR5 PAM EC₅₀: +++++.

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid,ethynyltrimethylsilane, and 2- bromo-5-fluoropyrimidine according toGeneral Experimentals C6, B1, and A2. MS (ESI+): 349 (M + H⁺); ¹H NMR(300 MHz, CDCl₃) δ 8.67 (s, 2H), 8.28 (d, J = 8.2 Hz, 1H), 7.90 (s, 1H),7.65 (d, J = 8.31 Hz, 1H), 3.84 (s, 2H), 3.07-3.02 (t, J = 7.1 Hz, 2H),1.81-1.77 (t, J = 7.1 Hz, 2H), 1.13 (s, 6H). mGluR5 PAM EC₅₀: +++.

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid,ethynyltrimethylsilane, and 2- bromothiazolo[5,4-b]pyridine according toGeneral Experimentals C6, B1, and A2. MS (ESI+): 387 (M + H⁺); ¹H NMR(300 MHz, CDCl₃) δ 8.80-8.60 (m, 1H), 8.37-8.30 (m, 2H), 7.90 (s, 1H),7.67-7.64 (dd, J = 8.2, 1.4 Hz, 1H), 7.54-7.50 (m, 1H), 3.85 (s, 2H),3.08- 3.03 (t, J = 7.1 Hz, 2H), 1.81-1.76 (t, J = 7.1 Hz, 2H), 1.12 (s,6H).

Synthesized from tert-butyl 2-oxa-6- azaspiro[3.5]nonane-6-carboxylate,2-amino-4- bromobenzoic acid, and 2-ethynylpyridine according to GeneralExperimentals C4, F3, B1, and A1. mGluR5 PAM EC₅₀: ++++. Fold shift at 1μM: +++.

Synthesized from tert-butyl 3-oxopiperidine-1- carboxylate,2-amino-4-bromobenzoic acid, and 2- ethynylpyridine according to GeneralExperimentals G22, G24, C4, F3, B1 and A1. MS (ESI+): 364 (M + H⁺). ¹HNMR (300 MHz, CD₃OD): δ 8.60 (d, J = 4.7 Hz, 1H), 8.24 (d, J = 8.2 Hz,1H), 7.95-7.89 (m, 1H), 7.85-7.84 (d, J = 1.0 Hz, 1H), 7.75-7.67 (m,2H), 7.50- 7.45 (m, 1H), 4.28-4.11 (m, 2H), 3.21-3.11 (m, 2H), 2.24-2.01(m, 2H), 1.64-1.48 (m, 2H). mGluR5 PAM EC₅₀: +++++. Fold shift at 1 μM:+++.

Synthesized from benzyl 7,7-difluoro-1-methyl-3-azabicyclo[4.1.0]heptane-3-carboxylate, 2-amino-4- bromobenzoic acid,and 2-ethynylpyridine according to General Experimentals F7, F6, C4, F3,B1 and A1. MS (ESI+): 364 (M + H⁺). ¹H NMR (300 MHz, CDCl₃): δ 8.67 (d,J = 3.9 Hz, 1H), 8.27 (d, J = 8.3 Hz, 1H), 7.86 (d, J = 1.2 Hz, 1H),7.71-7.59 (m, 3H), 7.33-7.28 (m, 1H), 5.10-5.04 (dd, J = 14.7, 3.6 Hz,1H), 3.44 (d, J = 14.7 Hz, 1H), 3.37-3.28 (m, 1H), 2.77-2.69 (dd, J =16.5, 7.2 Hz, 1H), 1.72-1.63 (m, 1H), 1.36 (d, J = 1.0 Hz, 3H). mGluR5PAM EC₅₀: +++++. Fold shift at 1 μM: +++.

Synthesized from but-2-yn-1-ol, 3-bromoprop-1-ene, 2-amino-4-bromobenzoic acid, and 2-ethynylpyridine according to GeneralExperimentals G21, H5, C2, B1, and A1. MS (ESI+): m/z 328 (M + H⁺); ¹HNMR (300 MHz, DMSO-d₆): δ 8.67 (d, J = 4.8 Hz, 1H), 8.17 (d, J = 8.2 Hz,1H), 7.97-7.91 (t, J = 7.8 Hz, 1H), 7.84 (s, 1H), 7.77 (d, J = 7.8 Hz,1H), 7.70-7.67 (dd, J = 8.2, 1.4 Hz, 1H), 7.52-7.48 (m, 1H), 4.44 (d, J= 13.9 Hz, 1H), 3.87 (d, J = 13.9 Hz, 1H), 3.41-3.34 (dd, J = 16.5, 3.9Hz, 1H), 3.05-2.99 (dd, J = 16.5, 3.4 Hz, 1H), 1.24 (s, 3H), 1.21-1.18(m, 1H), 0.53-0.47 (m, 2H).

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid, and1-ethynyl-2-fluorobenzene according to General Experimentals C6, B1, andA1. MS (ESI+): m/z 347 (M + H⁺); ¹H NMR (300 MHz, CDCl3) δ 8.27-8.24 (d,J = 8.25 Hz, 1H), 7.81 (s, 1H), 7.62-7.55 (m, 2H), 7.41-7.34 (m, 1H),7.20-7.12 (m, 2H), 3.84 (s, 2H), 3.06-3.02 (t, J = 7.14 Hz, 2H), 1.79-1.75 (t, J = 6.99 Hz, 2H), 1.13 (s, 6H). mGluR5 PAM EC₅₀: ++++.

Synthesized isobutyronitrile, 2-amino-4-bromobenzoic acid,ethynyltrimethylsilane, and 1-bromo-4- fluorobenzene according toGeneral Experimentals C6, B1, and A2. MS (ESI+): 347 (M + H⁺); ¹H NMR(300 MHz, CDCl₃) δ 8.25 (d, J = 8.3 Hz, 1H), 7.76 (s, 1H), 7.59-7.53 (m,3H), 7.12-7..06 (t, J = 8.6 Hz, 2 H), 3.84 (s, 2H), 3.06-3.02 (t, J =7.1 Hz, 2H), 1.79-1.75 (t, J = 7.1 Hz, 2H), 1.13 (s, 6H). mGluR5 PAMEC₅₀: ++++.

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid,ethynyltrimethylsilane, and 2- bromo-3-fluoropyridine according toGeneral Experimentals C6, B1, and A2. MS (ESI+): 348 (M + H⁺); ¹H NMR(300 MHz, CDCl₃) δ 8.50-8.48 (m, 1H), 8.27 (d, J = 8.3 Hz, 1H), 7.88 (s,1H), 7.63 (d, J = 8.2 Hz, 1H), 7.54-7.48 (td, J = 8.5, 1.2 Hz, 1H),7.37- 7.32 (m, 1H), 3.84 (s, 2H), 3.07-3.02 (t, J = 7.1 Hz, 2H),1.80-1.75 (t, J = 7.1 Hz, 2H), 1.12 (s, 6H). mGluR5 PAM EC₅₀: +++++.

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid,ethynyltrimethylsilane, and 3- bromo-2-fluoropyridine according toGeneral Experimentals C6, B1, and A2. MS (ESI+): 348 (M + H⁺); ¹H NMR(300 MHz, CDCl₃) δ 8.28-8.22 (m, 2H), 8.00-7.94 (m, 1H), 7.81 (s, 1H),7.60-7.57 (m, 2H), 3.84 (s, 2H), 3.07-3.02 (t, J = 7.1 Hz, 2H),1.80-1.75 (t, J = 7.1 Hz, 2H), 1.13 (s, 6H). mGluR5 PAM EC₅₀: +++++.

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid,ethynyltrimethylsilane, and 5- bromo-2-fluoropyridine according toGeneral Experimentals C6, B1, and A2. MS (ESI+): 348 (M + H⁺); ¹H NMR(300 MHz, CDCl₃): δ 8.45 (s, 1H), 8.26 (d, J = 8.2 Hz, 1H), 7.99-7.93(td, J = 8.3, 2.2 Hz, 1H), 7.78 (s, 1H), 7.56-7.53 (dd, J = 8.2, 1.3 Hz,1H), 7.01-6.97 (dd, J = 8.2, 2.7 Hz, 1H), 3.84 (s, 2H), 3.07- 3.02 (t, J= 7.1 Hz, 2H), 1.80-1.75 (t, J = 7.1 Hz, 2H), 1.13 (s, 6H). mGluR5 PAMEC₅₀: +++++.

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid,ethynyltrimethylsilane, and 3- bromo-5-fluoropyridine according toGeneral Experimentals C6, B1, and A2. MS (ESI+): 348 (M + H⁺); ¹H NMR(300 MHz, CDCl₃) δ 8.63 (s, 1H), 8.48 (s, 1H), 8.27 (d, J = 9.2 Hz, 1H),7.79 (s, 1H), 7.60- 7.55 (t, J = 8.7 Hz, 2H), 3.84 (s, 2H), 3.07-3.02(t, J = 7.1 Hz, 2H), 1.79-1.75 (t, J = 7.0 Hz, 2H), 1.13 (s, 6H). mGluR5PAM EC₅₀: +++++.

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid,ethynyltrimethylsilane, and 3- bromo-4-fluoropyridine according toGeneral Experimentals C6, B1, and A2. MS (ESI+): 348 (M + H⁺); ¹H NMR(300 MHz, CDCl₃): δ 8.80 (d, J = 9.4 Hz, 1H), 8.60-8.56 (m, 1H), 8.27(d, J = 8.2 Hz, 1H), 7.83 (s, 1H), 7.60-7.57 (dd, J = 8.3, 1.4 Hz, 1H),7.15- 7.10 (m, 1H), 3.84 (s, 2H), 3.07-3.02 (t, J = 7.1 Hz, 2H),1.80-1.75 (t, J = 7.1 Hz, 2H), 1.12 (s, 6H). mGluR5 PAM EC₅₀: +++++.

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid,ethynyltrimethylsilane, and HCl salt of 4-bromo-3-fluoropyridineaccording to General Experimentals C6, B1, and A2. MS (ESI+): 348 (M +H⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.56 (s, 1H), 8.46-8.45 (d, J = 4.86 Hz,1H), 8.30-8.27 (d, J = 8.25 Hz, 1H), 7.84 (s, 1H), 7.60-7.58 (d, J =8.28 Hz, 1H), 7.48-7.44 (t, J = 6.15 Hz, 1H), 3.84 (s, 2H), 3.07-3.02(t, J = 7.11 Hz, 2H), 1.80-1.75 (t, J = 7.08 Hz, 2H), 1.13 (s, 6H).mGluR5 PAM EC₅₀: +++++.

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid,ethynyltrimethylsilane, and 4- bromo-2-fluoropyridine according toGeneral Experimentals C6, B1, and A2. MS (ESI+): 348 (M + H⁺): ¹H NMR(300 MHz, CDCl₃) δ 8.30-8.25 (t, J = 8.4 Hz, 2H), 7.80 (s, 1H),7.58-7.55 (dd, J = 8.2, 1.4 Hz, 1H), 7.35-7.32 (m, 1H), 7.09 (s, 1H),3.84 (s, 2H), 3.07- 3.02 (t, J = 7.1 Hz, 2H), 1.80-1.75 (t, J = 7.1 Hz,2H), 1.13 (s, 6H). mGluR5 PAM EC₅₀: +++++.

Synthesized from benzyl 7,7-difluoro-1-methyl-3-azabicyclo[4.1.0]heptane-3-carboxylate, 2-amino-4- bromobenzoic acid,and 2-ethynylpyridine according to General Experimentals F7, F6, C4, F3,B1 and A1. MS (ESI+): 400, 402 (M + H⁺). ¹H NMR (300 MHz, CD₃OD): δ 8.61(d, J = 4.8 Hz, 1H), 8.25 (d, J = 8.1 Hz, 1H), 7.96-7.88 (m, 2H),7.75-7.68 (m, 2H), 7.51-7.46 (m, 1H), 4.64-4.57 (m, 1H), 3.94-3.84 (m,1H), 3.43- 3.38 (m, 1H), 3.09-2.91 (m, 1H), 2.52-2.42 (m, 1H), 2.08-1.95(m, 1H), 1.63-1.60 (d, J = 7.4 Hz, 3H).

Synthesized from 1-(tert-butoxycarbonyl)-3-methylpiperidine-3-carboxylic acid, 2-amino-4- bromobenzoic acid and2-ethynylpyridine according to General Experimentals G1, C4, F3, B1,G31, E1 and A1. MS (ESI+): 348 (M + H⁺); ¹H NMR (300 MHz, CDCl₃) δ8.68-8.67 (d, J = 4.35 Hz, 1H), 8.27-8.24 (d, J = 8.22 Hz, 1H), 7.85 (s,1H), 7.77-7.71 (m, 1H), 7.66- 7.59 (m, 2H), 7.33-7.30 (m, 1H), 4.67-4.62(d, J = 13.80 Hz, 1H), 4.47-4.35 (dd, J = 19.73, 14.66 Hz, 1H), 3.12-3.05 (m, 2H), 2.14-2.05 (m, 2H), 1.97-1.84 (m, 2H), 1.51-1.44 (d, J =21.90 Hz, 3H). mGluR5 PAM EC₅₀: +++++. Fold shift at 1 μM: +++.

Synthesized from 1-(tert-butoxycarbonyl)-3-methylpiperidine-3-carboxylic acid, 2-amino-4- bromobenzoic acid, and2-ethynylpyridine according to General Experimentals G1, C4, F3, B1,G31, G13 and A1. MS (ESI+): 360 (M + H⁺); ¹H NMR (300 MHz, CDCl₃) δ8.67-8.66 (dd, J = 4.83, 0.63 Hz, 1H), 8.27- 8.24 (d, J = 8.25 Hz, 1H),7.84 (s, 1H), 7.76-7.70 (dd, J = 7.80, 1.80 Hz, 1H), 7.63-7.58 (t, J =7.77 Hz, 2H), 7.32-7.29 (m, 1H), 4.06-4.01 (d, J = 14.10 Hz, 1H),3.93-3.83 (d, J = 13.80 Hz, 1H), 3.35 (s, 3H), 3.26-3.19 (m, 2H),2.99-2.95 (t, J = 7.04 Hz, 2H), 2.01-1.92 (m, 1H), 1.68-1.59 (m, 1H),1.07 (s, 3H). mGluR5 PAM EC₅₀: ++++. Fold shift at 1 μM: +++.

Synthesized from but-2-yn-1-ol, 3-bromoprop-1-ene, 2-amino-4-bromobenzoic acid and 2-ethynylpyridine according to GeneralExperimentals G21, H5, C2, B1, and A1. MS (ESI+): m/z 328 (M + H⁺): ¹HNMR (300 MHz, DMSO-d₆) δ 8.68 (d, J = 4.5 Hz, 1H), 8.17 (d, J = 8.2 Hz,1H), 7.99-7.93 (t, J = 7.8 Hz, 1H), 7.89 (s, 1H), 7.79 (d, J = 7.8 Hz,1H), 7.70 (d, J = 8.3 Hz, 1H), 7.55- 7.52 (m, 1H), 4.57-4.51 (dd, J =14.2, 3.1 Hz, 1H), 4.07- 4.02 (dd, J = 14.1, 3.0 Hz, 1H), 3.26-3.03 (m,2H), 1.34- 1.31 (m, 1H), 1.23 (s, 3H), 0.53-0.47 (m, 2H). mGluR5 PAMEC₅₀: +++++. Fold shift at 1 μM: +++.

Synthesized from 1-(tert-butoxycarbonyl)-3-methylpiperidine-3-carboxylic acid, 2-amino-4- bromobenzoic acid, and2-ethynylpyridine according to General Experimentals G1, C4, F3, B1, G31and A1. MS (ESI+): 346 (M + H⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.68 (brs,1H), 8.27-8.25 (d, J = 8.16 Hz, 1H), 7.87 (s, 1H), 7.75-7.73 (m, 1H),7.65-7.62 (d, J = 81.9 Hz, 2H), 7.37-7.31 (m, 1H), 4.26-4.22 (d, J =13.84 Hz, 1H), 3.80-3.76 (d, J = 13.89 Hz, 1H), 3.44 (s, 2H), 3.03-2.98(t, J = 7.01 Hz, 2H), 1.92-1.80 (m, 1H), 1.76-1.67 (m, 1H), 1.13 (s,3H). mGluR5 PAM EC₅₀: +++. Fold shift at 1 μM: +++.

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid,ethynyltrimethylsilane and 2-bromo- 3-methoxypyridine according toGeneral Experimentals C6, B1 and A2. MS (ESI+): 360 (M + H⁺); ¹H NMR(300 MHz, CDCl₃) δ 8.26-8.24 (d, J = 8.31 Hz, 2H), 7.89 (s, 1H),7.66-7.63 (d, J= 8.28 Hz, 1H), 7.32-7.29 (m, 2H), 3.97 (s, 3H), 3.84 (s,2H), 3.08-3.03 (t, J = 7.10 Hz, 2H), 1.79-1.74 (t, J = 7.11 Hz, 2H),1.12 (s, 6H).

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid,ethynyltrimethylsilane and 2-bromo- 6-methoxypyridine according toGeneral Experimentals C6, B1 and A2. MS (ESI+): 360 (M + H⁺); ¹H NMR(300 MHz, CDCl₃) δ 8.27-8.24 (d, J = 8.40 Hz, 1H), 7.87 (brs, 1H),7.64-7.56 (m, 2H), 7.22-7.19 (d, J = 7.23 Hz, 1H), 6.79-6.76 (d, J =8.40 Hz, 1H), 4.01 (s, 3H), 3.84 (s, 2H), 3.07 (brs, 2H), 1.80-1.75 (t,J = 6.95 Hz, 2H), 1.13 (s, 6H). mGluR5 PAM EC₅₀: +++. Fold shift at 1μM: ++.

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid,ethynyltrimethylsilane and 2-bromo- 4-methoxypyridine according toGeneral Experimentals C6, B1 and A2. MS (ESI+): 360 (M + H⁺); ¹H NMR(300 MHz, CDCl₃) δ 8.48-8.46 (d, J = 5.76 Hz, 1H) ,8.27- 8.24 (d, J =8.29 Hz, 1H), 7.85-7.84 (d, J = 1.02 Hz, 1H), 7.63-7.60 (dd, J = 8.24,1.40 Hz, 1H), 7.14-7.13 (d, J = 2.43 Hz, 1H), 6.86-6.83 (dd, J = 5.81,2.51 Hz, 1H), 3.92 (s, 3H), 3.84 (s, 2H), 3.07-3.02 (t, J = 7.13 Hz,2H), 1.79-1.74 (t, J = 7.20 Hz, 2H), 1.12 (s, 6H). mGluR5 PAM EC₅₀: +++.Fold shift at 1 μM: +.

Synthesized from dimethyl malonate, 1,4-dichlorobut-2- ene,2-amino-4-bromobenzoic acid and 2- ethynylpyridine according to GeneralExperimentals H18 and A1. MS (ESI+): 344 (M + H⁺); ¹H NMR (300 MHz,CDCl₃) : δ 8.67 (d, J = 4.6 Hz, 1H), 8.22 (d, J = 8.2 Hz, 1H), 7.83 (s,1H), 7.77-7.71 (td, J = 7.6, 1.7 Hz, 1H), 7.61-7.51 (m, 2H), 7.33-7.29(m, 1H), 4.97-4.90 (m, 1H), 3.77 (d, J = 4.9 Hz, 2H), 3.27-3.16 (m, 1H),2.40- 2.30 (m, 2H), 2.11-2.04 (m, 1H), 1.33-1.24 (m, 2H). mGluR5 PAMEC₅₀: ++.

Synthesized from (R)-tert-butyl 2-(aminomethyl)pyrrolidine-1-carboxylate, 2-amino-4- bromobenzoic acid and2-ethynylpyridine according to General Experimentals H19, B1 and A1. MS(ESI+): m/z 343 (M + H⁺); ¹H NMR (300 MHz, DMSO-d₆) δ 8.69 (d, J = 4.7Hz, 1H), 8.24 (d, J = 8.2 Hz, 1H), 8.02-7.94 (m, 2H), 7.82-7.80 (m, 2H),7.56-7.52 (m, 1H), 4.62-4.44 (m, 3H), 4.29-4.20 (m, 2H), 3.72 (m, 1H),3.11 (m, 1H), 2.26 (m, 1H), 2.00 (m, 1H), 1.80 (m, 2H). mGluR5 PAM EC₅₀:+++.

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid,ethynyltrimethylsilane and 3- bromopyridazine according to GeneralExperimentals C6, B1 and A2. MS (ESI+): 331 (M + H⁺); ¹H NMR (300 MHz,CDCl₃) δ 9.21-9.19 (d, J = 3.54 Hz, 1H), 8.31- 8.29 (d, J = 8.25 Hz,1H), 7.94 (brs, 1H), 7.75-7.71 (m, 1H), 7.68-7.62 (m, 1H), 7.56-7.51 (m,1H), 3.85 (s, 2H), 3.11 (brs, 2H), 1.81-1.76 (t, J = 7.05 Hz, 2H), 1.14(s, 6H). mGluR5 PAM EC₅₀: +++. Fold shift at 1 μM: ++.

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid andethynyltrimethylsilane according to General Experimentals C6, B1 and A2.MS (ESI+): m/z 253 (M + H⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.30- 8.18 (m,1H), 7.80-7.70 (m, 1H), 7.50 (d, J = 8.3 Hz, 1H), 3.83 (s, 2H), 3.27 (s,1H), 3.10-2.90 (m, 2H), 1.85- 1.70 (m, 2H), 1.12 (s, 6H).

See PCT/US2010/061147.

See PCT/US2010/061147.

See PCT/US2010/061147.

See PCT/US2010/061147.

Synthesized from caprolactam, 2-amino-4-bromobenzoic acid, and2-bromoisonicotinonitrile according to General Experimentals B1 and A2.MS (ESI+): m/z 341 (MH⁺); ¹H NMR (300 MHz, CD₃OD): δ 8.88-8.86 (d, J =4.86 Hz, 1H), 8.42-8.39 (d, J = 8.28 Hz, 1H), 8.13 (s, 1H), 7.98-7.93(m, 2H), 7.84-7.81 (dd, J = 5.07, 1.44 Hz, 1H), 4.58-4.55 (m, 2H),3.38-3.33 (m, 2H), 2.06-1.90 (m, 6H). mGluR5 PAM EC₅₀: ++++.

Synthesized from tert-butyl 4-oxopiperidine-1- carboxylate,2-amino-4-bromobenzoic acid, and 2- ethynylpyridine according to GeneralExperimentals C2, B1, F3, H3, and A1. MS (ESI+): m/z 343 (M + H⁺); ¹HNMR (300 MHz, CD₃OD) δ 8.95-8.93 (d, J = 5.61 Hz, 1H), 8.72-8.67 (t, J =8.00 Hz, 1H), 8.38-8.34 (m, 2H), 8.15-8.10 (t, J = 6.90 Hz, 1H), 8.06(s, 1H), 7.90-7.87 (d, J = 8.25 Hz, 1H), 5.74-5.68 (d, J = 12.26 Hz,1H), 4.27- 4.21 (t, J = 8.13 Hz, 1H), 4.15-4.05 (m, 1H), 3.94-3.72 (m,5H), 3.61-3.53 (t, J = 12.58 Hz, 1H), 2.95-2.83 (m, 1H), 2.77-2.66 (m,1H). mGluR5 PAM EC₅₀: ++.

Synthesized as a mixture from 4-methylcyclohexanone,3-amino-5-bromopicolinic acid, and 2-ethynylpyridine according toGeneral Experimentals C2, B2, and A1. MS (ESI+): m/z 331 (MH⁺); ¹H NMR(300 MHz, CDCl₃): δ 8.96 (d, J = 1.2 Hz, 1H), 8.68 (d, J = 4.8 Hz, 1H),8.11-8.10 (m, 1H), 7.79-7.73 (m, 1H), 7.63-7.61 (m, 1H), 7.36-7.31 (m,1H), 5.12-4.70 (m, 1H), 3.91-3.76 (m, 1H), 3.08-2.97 (m, 2H), 2.05-1.93(m, 3H), 1.70-1.52 (m, 2H), 1.14-1.06 (m, 3H). mGluR5 PAM EC₅₀: +++. and

Synthesized from 3-(trifluoromethyl)cyclohexanone, 3-amino-5-bromopicolinic acid, and 2-ethynylpyridine according to GeneralExperimentals C2, B1, and A1. MS (ESI+): m/z 385 (MH⁺). mGluR5 PAM EC₅₀:+++.

Synthesized from 4-(trifluoromethyl)cyclohexanone, 3-amino-5-bromopicolinic acid, and 2-ethynylpyridine according to GeneralExperimentals C2, B1, and A1. MS (ESI+): m/z 385 (M + H⁺); ¹H NMR (300MHz, CD₃OD) δ 9.08 (s, 1H), 8.98-8.96 (d, J = 5.16 Hz, 1H), 8.71-8.66(td, J = 7.98, 1.43 Hz, 1H), 8.48 (s, 1H), 8.39- 8.36 (d, J = 7.98 Hz,1H), 8.15-8.11 (t, J = 6.15 Hz, 1H), 5.38-5.31 (dd, J = 14.77, 6.93 Hz,1H), 3.92-3.84 (dd, J = 14.70, 11.10 Hz, 1H), 3.51-3.33 (m, 2H),2.88-2.78 (m, 1H), 2.46-2.42 (m, 2H), 1.86-1.64 (m, 2H).

Synthesized from azepan-4-one, 3-amino-5- bromopicolinic acid, and2-ethynylpyridine according to General Experimentals F6, G8, E1, C4, F3,B1, and A1. MS (ESI+): m/z 349 (M + H⁺); ¹H NMR (300 MHz, CD₃OD) δ 9.04(s, 1H), 8.94-8.92 (d, J = 5.64 Hz, 1H), 8.65-8.60 (t, J = 7.89 Hz, 1H),8.42 (s, 1H), 8.34-8.31 (d, J = 7.92 Hz, 1H), 8.10-8.06 (t, J = 6.60 Hz,1H), 5.11- 5.04 (dd, J = 15.16, 5.64 Hz, 1H), 4.14-4.06 (t, J = 7.35 Hz,1H), 3.67-6.58 (t, J = 13.27 Hz, 1H), 3.02-2.95 (dd, J = 14.90, 7.16 Hz,1H), 2.34-2.28 (m, 2H), 2.07-1.93 (m, 2H), 1.48-1.41 (d, J = 21.10 Hz,3H).

Synthesized from 1,4-dioxa-8-azaspiro[4.6]undecan-9- one,2-amino-4-bromobenzoic acid, and 2- ethynylpyridine according to GeneralExperimentals B1, F2, G7, G13, and A1. MS (ESI+): m/z 346 (M + H ⁺); ¹HNMR (300 MHz, CDCl₃) δ 8.67-8.65 (d, J = 4.47 Hz, 1H), 8.25-8.22 (d, J =8.22 Hz, 1H), 7.82 (s, 1H), 7.76- 7.70 (td, J = 7.74, 1.68 Hz, 1H),7.63-7.57 (t, J = 8.40 Hz, 2H), 7.32-7.30 (m, 1H), 4.70-4.63 (m, 1H),4.26- 4.18 (m, 1H), 3.65-3.63 (m, 1H), 3.42 (s, 3H), 3.39-3.35 (m, 1H),2.88-2.81 (dd, J = 14.40, 8.40 Hz, 1H), 2.25- 2.09 (m, 2H), 1.96-1.81(m, 2H).

Synthesized from 4-methylcyclohexanone, 3-bromo-2- fluoroaniline, and2-ethynylpyridine according to General Experimentals C2, D1, B1, and A1.MS (ESI+): m/z 348 (M + H⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.92- 8.90 (d, J= 5.13 Hz, 1H), 8.64-8.59 (t, J = 8.34 Hz, 1H), 8.31-8.29 (d, J = 8.13Hz, 1H), 8.16-8.14 (d, J = 8.34 Hz, 1H), 8.09-8.05 (t, J = 7.17 Hz, 1H),7.88-7.83 (t, J = 7.20 Hz, 1H), 5.19-5.12 (dd, J = 15.61, 6.30 Hz, 1H),3.90-3.82 (t, J = 12.75 Hz, 1H), 3.61-3.45 (m, 1H), 2.15- 2.01 (m, 3H),1.47-1.29 (m, 3H), 1.05-1.03 (d, J = 6.60 Hz, 3H).

Synthesized from 4-ethylcyclohexanone, 2-amino-4- bromobenzoic acid, and2-ethynylpyridine according to General Experimentals C2, B1, and A1. MS(ESI+): m/z 344 (M + H⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.68-8.66 (d, J =4.44 Hz, 1H), 8.26-8.23 (d, J = 8.22 Hz, 1H), 7.83 (s, 1H), 7.76-7.71(td, J = 7.89, 1.71 Hz, 1H), 7.63-7.58 (t, J = 7.50 Hz, 1H), 7.33-7.30(m, 1H), 5.24-5.17 (dd, J = 14.40, 6.60 Hz, 1H), 3.63-3.55 (dd, J =14.40, 10.80 Hz, 1H), 3.18-2.99 (m, 2H), 2.19-2.14 (m, 2H), 1.44- 1.18(m, 4H), 0.96-0.92 (t, J = 7.43 Hz, 3H).

Synthesized from 4-ethylcyclohexanone, 3-amino-5- bromopicolinic acid,and 2-ethynylpyridine according to General Experimentals C2, B1, and A1.MS (ESI+): m/z 345 (M + H⁺); ¹H NMR (300 MHz, DMSO-d₆) δ 8.95- 8.86 (m,1H), 8.69 (broad, 1H), 8.24 (s, 1H), 8.02-7.97 (t, J = 7.68 Hz, 1H),7.86-7.83 (d, J = 7.65 Hz, 1H), 7.58-7.54 (t, J = 6.00 Hz, 1H),4.95-4.88 (dd, J = 14.40, 6.60 Hz, 1H), 3.75-3.71 (m, 1H), 3.22-3.13 (m,1H), 3.03-2.96 (m, 1H), 2.06-1.98 (m, 2H), 1.63 (broad, 1H), 1.32-1.09(m, 4H), 0.87-0.82 (t, J = 7.35 Hz, 3H).

Synthesized from 1,4-dioxa-8-azaspiro[4.6]undecan-9- one,2-amino-4-bromobenzoic acid, and 2- ethynylpyridine according to GeneralExperimentals B1, F2, E2, and A1. MS (ESI+): m/z 352 (M + H⁺); ¹H NMR(300 MHz, CDCl₃) δ 8.69-8.67 (d, J = 4.95 Hz, 1H), 8.27-8.24 (d, J =8.25 Hz, 1H), 7.88 (s, 1H), 7.77-7.71 (td, J = 7.71, 1.68 Hz, 1H),7.68-7.65 (dd, J = 8.25, 1.35 Hz, 1H), 7.61-7.59 (d, J = 7.83 Hz, 1H),7.34-7.29 (m, 1H), 4.49-4.46 (t, J = 4.41 Hz, 2H), 3.19-3.15 (t, J =5.88 Hz, 2H), 2.42-2.22 (m, 4H). mGluR5 PAM EC₅₀: ++++, Fold shift at 10μM: +++.

Synthesized from 1,4-dioxa-8-azaspiro[4.6]undecan-9- one,3-amino-5-bromopicolinic acid, and 2- ethynylpyridine according toGeneral Experimentals B1, F2, E2, and A1. MS (ESI+): m/z 353 (M + H⁺);¹HNMR (300 MHz, CD₃OD) δ 9.06 (brs, 1H), 8.98-8.96 (d, J = 5.55 Hz, 1H),8.73-8.67 (td, J = 7.98, 1.41 Hz, 1H), 8.47 (s, 1H), 8.40-8.37 (d, J =8.01 Hz, 1H), 8.17-8.12 (m, 1H), 4.57-4.55 (m, 2H), 3.31-3.27 (m, 2H),2.47-2.35 (m, 4H). mGluR5 PAM EC₅₀: ++.

Synthesized from azepan-4-one, 2-amino-4- bromobenzoic acid, and2-ethynylpyridine according to General Experimentals F6, G8, E1, C4, F3,B1, and A1. MS (ESI+): m/z 362 (M + H⁺); ¹H NMR (300 MHz, CD₃OD) δ8.90-8.88 (d, J = 5.13 Hz, 1H), 8.57-8.52 (t, J = 7.38 Hz, 1H),8.45-8.42 (d, J = 8.43 Hz, 1H), 8.26- 8.24 (d, J = 7.74 Hz, 1H),8.07-7.98 (m, 3H), 5.17-5.10 (dd, J = 14.7, 5.10 Hz, 1H), 4.16-4.07 (t,J = 11.71 Hz, 1H), 3.78-3.69 (t, J = 14.46 Hz, 1H), 3.19-3.11 (dd, J =15.60, 6.90 Hz, 1H), 2.46-2.26 (m, 2H), 2.20-1.91 (m, 2H), 1.82-1.68 (m,2H), 1.03-0.98 (t, J = 7.50 Hz, 3H). mGluR5 PAM EC₅₀: ++++.

Synthesized from azepan-4-one, 3-amino-5- bromopicolinic acid, and2-ethynylpyridine according to General Experimentals F6, G8, E1, C4, F3,B1, and A1. MS (ESI+): m/z 363 (M + H⁺); ¹H NMR (300 MHz, CD₃OD) δ 9.03(brs, 1H), 8.92-8.91 (d, J = 5.25 Hz, 1H), 8.61-8.56 (t, J = 7.64 Hz,1H), 8.40 (s, 1H), 8.30-8.28 (d, J = 8.46 Hz, 1H), 8.07-8.02 (t, J =7.20 Hz, 1H), 5.14- 5.07 (dd, J = 14.85, 6.15 Hz, 1H), 4.14-4.10 (t, J =11.20 Hz, 1H), 3.67-3.58 (t, J = 13.93 Hz, 1H), 3.03-2.95 (dd, J =17.90, 6.60 Hz, 1H), 2.34-2.29 (m, 2H), 2.05-1.85 (m, 2H), 1.78-1.69 (m,2H), 1.02-0.97 (t, J = 7.52 Hz, 3H). mGluR5 PAM EC₅₀: +++.

Synthesized from 4-methylcyclohexanone, 2-amino-4- bromobenzoic acid,and 2-bromoisonicotinonitrile according to General Experimentals C2, B1,and A2. MS (ESI+): m/z 355 (M + H⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.88-8.86(d, J = 5.0 Hz, 1H), 8.41-8.39 (d, J = 8.3 Hz, 1H), 8.12 (s, 1H),7.98-7.93 (m, 2H), 7.83-7.81 (dd, J = 5.1, 1.4 Hz, 1H), 5.23-5.17 (dd, J= 14.3, 6.4 Hz, 1H), 3.95-3.86 (m, 1H), 3.52-3.43 (m, 1H), 2.24-2.05 (m,3H), 1.64-1.56 (m, 1H), 1.41-1.30 (m, 2H), 1.07- 1.05 (d, J = 6.5 Hz,3H). mGluR5 PAM EC₅₀: +++.

Synthesized from 4-methylcyclohexanone, 2-amino-4- bromobenzoic acid,and 2-ethynylpyridine according to General Experimentals C2, B4, B2, andA1. MS (ESI+): m/z 329 (M + H⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.91 (d, J =5.4 Hz, 1H), 8.69-8.65 (m, 1H), 8.37-8.30 (m, 2H), 8.13-8.08 (m, 1H),7.97 (s, 1H), 7.73-7.70 (dd, J = 8.4, 1.5 Hz, 1H), 6.62 (s, 1H),5.25-5.05 (m, 1H), 3.85- 3.69 (m, 1H), 3.04-2.96 (m, 2H), 2.16-2.09 (m,2H), 2.05-1.82 (m, 1H), 1.26-1.17 (m, 2H), 1.01 (d, J = 6.3 Hz, 3H).

Synthesized from 4-methylcyclohexanone, 3-bromo-4- methylaniline, and2-ethynylpyridine according to General Experimentals D1, B1, and A1. MS(ESI+): m/z 344 (M + H⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.92-8.90 (d, J =5.70 Hz, 1H), 8.60-8.55 (td, J = 7.95, 1.49 Hz, 1H), 8.30-8.27 (m, 2H),8.15-8.14 (m, 1H), 8.05-8.00 (m, 1H), 5.22-5.16 (dd, J = 14.74, 6.12 Hz,1H), 5.11- 5.05 (m, 1H), 3.94-3.86 (m, 1H), 3.63-3.56 (m, 1H), 2.59 (s,3H), 2.18-2.11 (m, 3H), 1.54-1.49 (m, 1H), 1.38-1.33 (m, 1H), 1.08-1.05(d, J = 6.54 Hz, 3H).

Synthesized from 4-methylcyclohexanone, 3-bromo-5- methylaniline, and2-ethynylpyridine according to General Experimentals D1, B1, and A1. MS(ESI+): m/z 344 (M + H⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.92-8.90 (d, J =5.13 Hz, 1H), 8.62-8.56 (td, J = 7.95, 1.46 Hz, 1H), 8.29-8.26 (d, J =7.98 Hz, 1H), 8.07-8.03 (t, J = 7.02 Hz, 1H), 7.91 (s, 1H), 7.84 (s,1H), 5.18-5.11 (dd, J = 15.00, 6.72 Hz, 1H), 3.91-3.82 (dd, J = 14.40,11.10 Hz, 1H), 3.50-3.41 (t, J = 12.33 Hz, 1H), 3.27-3.22 (m, 1H), 2.92(s, 3H), 2.23-2.04 (m, 3H), 1.64-1.52 (q, 1H), 1.41-1.31 (m, 1H),1.07-1.04 (d, J = 6.42 Hz, 3H). mGluR5 PAM EC₅₀: +++.

Synthesized from 1,4-dioxa-8-azaspiro[4.6]undecan-9- one,3-amino-5-bromopicolinic acid, and 2- ethynylpyridine according toGeneral Experimentals B1, F2, G7, G13, and A1. MS (ESI+): m/z 347 (M +H⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.67 (s, 1H), 8.40 (s, 1H), 7.82-7.72 (m,3H), 7.61-7.55 (m, 1H), 4.93-4.87 (dd, J = 14.40, 6.90 Hz, 1H), 4.67 (s,1H), 3.52-3.48 (m, 1H), 3.29-3.19 (m, 1H), 2.99 (s, 3H), 2.34 (s, 3H),2.22-2.13 (m, 1H), 1.97-1.95 (m, 1H). mGluR5 PAM EC₅₀: ++.

Synthesized from tert-butyl 3-oxoazepane-1-carboxylate,2-amino-4-bromobenzoic acid, and 2-ethynylpyridine according to GeneralExperimentals G5, E1, C4, B1, and A1. MS (ESI+): m/z 348 (M + H⁺); ¹HNMR (300 MHz, CD₃OD): δ 8.68-8.66 (d, J = 4.20 Hz, 1H), 8.27-8.24 (d, J= 78.22 Hz, 1H), 7.84 (s, 1H), 7.77-7.71 (td, J = 7.98, 1.74 Hz, 1H),7.65-7.62 (dd, 8.25, 1.47 Hz, 1H), 7.61-7.58 (d, J = 7.80 Hz, 1H),7.34-7.30 (m, 1H), 4.66-4.61 (m, 1H), 4.47-4.35 (m, 1H), 3.10-3.04 (m,2H), 2.14-2.00 (m, 2H), 1.96-1.83 (m, 2H), 1.51-1.44 (d, J = 21.79 Hz,3H).

Synthesized from tert-butyl 3-oxoazepane-1-carboxylate,3-amino-5-bromopicolinic acid, and 2-ethynylpyridine according toGeneral Experimentals G8, E1, C4, B1, and A1. MS (ESI+): m/z 349 (M +H⁺); mGluR5 PAM EC₅₀: ++.

Synthesized from 1,4-dioxaspiro[4.5]decan-7-one, 3-amino-5-bromopicolinic acid, and 2-ethynylpyridine according to GeneralExperimentals C2, B1, F2, E2, and A1. MS (ESI+): m/z 353 (M + H⁺);mGluR5 PAM EC₅₀: +++.

Synthesized from 1,4-dioxaspiro[4.5]decan-7-one, 3-amino-5-bromopicolinic acid, and 2-ethynylpyridine according to GeneralExperimentals C2, B1, and A1. MS (ESI+): m/z 375 (M + H⁺);

Synthesized from 1,4-dioxaspiro[4.5]decan-8-one, 2- amino-4-bromobenzoicacid, and 2-ethynylpyridine according to General Experimentals G9, E2,F2, C2, B1, and A1. MS (ESI+): m/z 366 (M + H⁺). and

Synthesized from 1,4-dioxaspiro[4.5]decan-8-one, 3-amino-5-bromopicolinic acid, and 2-ethynylpyridine according to GeneralExperimentals G9, E2, F2, C2, B1, and A1. MS (ESI+): m/z 367 (M + H⁺);¹H NMR (300 MHz, CDCl₃) δ 8.98 (d, J = 1.9 Hz, 1H), 8.68 (), 8.13 (s,1H), 7.79-7.74 (m, 1H), 7.64-7.62 (m, 1H), 7.36-7.32 (m, 1H), 4.78-4.09(m, 2H), 3.16-2.89 (m, 2H), 2.41- 2.12 (m, 3H), 1.16 (d, J = 6.8 Hz,1H), 1.11 (d, J = 6.8 Hz, 1H). and

Synthesized from tetrahydroisobenzofuran-1,3-dione, 2-amino-4-bromobenzoic acid, and 2-ethynylpyridine according to GeneralExperimentals H2, C2, B1, and A1. MS (ESI+): m/z 358 (M + H⁺); ¹H NMR(300 MHz, CDCl₃) δ 8.67 (d, J = 4.5 Hz, 1H), 8.27-8.23 (dd, J = 8.2, 2.6Hz, 1H), 7.84 (s, 1H), 7.77-7.71 (m, 1H), 7.65-7.58 (m, 2H), 7.33-7.31(m, 1H), 4.84-4.70 (m, 1H), 4.15- 4.06 (m, 1H), 4.05-3.95 (m, 2H),3.86-3.70 (m, 2H), 3.37-3.17 (m, 1H), 3.09-3.04 (m, 1H), 2.64-2.51 (m,2H), 2.12-1.97 (m, 2H). and

Synthesized from 1-(tert-butoxycarbonyl)-4- oxopyrrolidine-2-carboxylicacid, 2-amino-4- bromobenzoic acid, and 2-ethynylpyridine according toGeneral Experimentals G1, E2, G2, G5, F3, G10, G11, G12, C2, B1, and A1.Example 3.33a. MS (ESI+): m/z 393 (M + H⁺); ¹H NMR (300 MHz, CD₃OD): δ8.94-8.93 (d, J = 5.16 Hz, 1H), 8.71-8.65 (td, J = 7.97, 1.50 Hz, 1H),8.40-8.33 (m, 2H), 8.14-8.08 (td, J = 5.91, 1.11 Hz, 1H), 8.06 (s, 1H),7.91-7.88 (dd, J = 8.25, 1.47 Hz, 1H), 5.56-5.51 (d, J = 15.90 Hz, 1H),4.28-4.16 (m, 2H), 3.99-3.92 (m, 2H), 3.81-3.66 (m, 2H), 3.52-3.42 (m,2H), 3.11-2.97 (m, 1H), 2.76-2.67 (m, 1H). mGluR5 PAM EC₅₀: +++. and

Example 3.33b. MS (ESI+): m/z 393 (M + H⁺); ¹H NMR (300 MHz, CD₃OD): δ8.95-8.93 (d, J = 5.97 Hz, 1H), 8.72-8.66 (td, J = 7.99, 1.46 Hz, 1H),8.39-8.34 (t, J = 8.04 Hz, 2H), 8.15-8.10 (t, J = 7.32 Hz, 1H), 8.06 (s,1H), 7.90-7.87 (dd, J = 8.25, 1.38 Hz, 1H), 5.55-5.48 (dd, J = 16.39,5.22 Hz, 1H), 4.28-4.14 (m, 2H), 4.13- 3.91 (m, 3H), 3.78-3.65 (m, 1H),3.53-3.37 (m, 2H), 3.11-2.97 (m, 1H), 2.83-2.62 (m, 1H).

Synthesized from 1-tert-butyl 2-methyl pyrrolidine-1,2- dicarboxylate,2-amino-4-bromobenzoic acid, and 2- ethynylpyridine according to GeneralExperimentals G9, G2, G5, F3, G10, G11, G12, C2, B1, and A1. MS (ESI+):m/z 371 (M + H⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.92 (brs, 1H), 8.71-8.60(t, J = 8.2 Hz, 1H), 8.41-8.29 (m, 2H), 8.16-8.05 (m, 2H), 7.87-7.84 (d,J = 8.1 Hz, 1H), 3.92-3.72 (m, 3H), 3.60-3.47 (m, 2H), 2.46-2.41 (m,2H), 2.66 (brs, 3H), 1.59-1.47 (m, 2H), 1.35-1.30 (m, 1H), 1.21-1.14 (m,2H). mGluR5 PAM EC₅₀: +.

Synthesized as mixture of diasteriomers and enantiomers from methyl5-oxoazepane-4-carboxylate, 2-amino-4- bromobenzoic acid, and2-ethynylpyridine according to General Experimentals F5, G9, G12, F5,G7, E1, C4, F3, B1, and A1. MS (ESI+): m/z 348 (M + H)⁺.

Synthesized from 1,4-dioxaspiro[4.5]decan-8-one, 3-amino-5-bromopicolinic acid, and 2-ethynylpyridine according to GeneralExperimentals G9, E2, F2, C2, B1, and A1. MS (ESI+): m/z 367 (M + H⁺).

Synthesized from oxetan-3-one, nitromethane,(carbethoxymethylene)-triphenylphosphorane, 2-amino- 4-bromobenzoicacid, and 2-ethynylpyridine according to General Experimentals H14 andA1. MS (ESI+): m/z 358 (M + H⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.67 (d, J =4.7 Hz, 1H), 8.27 (d, J = 8.2 Hz, 1H), 7.83 (s, 1H), 7.77- 7.71 (m, 1H),7.66-7.58 (m, 2H), 7.33-7.30 (m, 1H), 4.68 (s, 2H), 4.58 (d, J = 5.9 Hz,2H), 4.30 (d, J = 5.9 Hz, 2H), 3.06-3.02 (m, 2H), 2.23-2.19 (m, 2H),1.92-1.91 (m, 2H). mGluR5 PAM EC₅₀: ++++.

Synthesized from methyl(triphenyl)phosphonium bromide, tert-butyl3-oxoazepane-1-carboxylate, 2- amino-4-bromobenzoic acid and2-ethynylpyridine according to General Experimentals G22, G24, C4, F3,B1 and A1. MS (ESI+): 378 (M + H⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.67 (d, J= 4.2 Hz, 1H), 8.22 (d, J = 8.2 Hz, 1H), 7.85 (s, 1H), 7.77-7.71 (td, J= 7.7, 1.6 Hz, 1H), 7.66-7.58 (m, 2H), 7.33-7.31 (m, 1H), 5.05 (d, J =15.1 Hz, 1H), 3.97 (d, J = 15.0 Hz, 1H), 3.25-3.07 (m, 2H), 2.18-2.04(m, 2H), 1.82-1.73 (m, 2H), 1.46-1.38 (m, 1H), 1.09-1.01 (m, 1H). mGluR5PAM EC₅₀: ++++. Fold shift at 1 μM: +++.

Synthesized from 4,4-dimethylcyclohex-2-enone; 2- amino-4-bromobenzonicand 2-ethynylpyridine according to General Experimentals C2, B1 and A1.MS (ESI+): 342 (M + H⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.59-8.58 (d, J =4.23 Hz, 1H), 8.18-8.15 (d, J = 8.22 Hz, 1H), 7.82 (s, 1H), 7.68-7.62(m, 1H), 7.55-7.49 (t, J = 8.19 Hz, 2H), 7.24-7.21 (m, 1H), 6.28-6.24(d, J = 12.96 Hz, 1H), 6.03-5.99 (d, J = 12.96 Hz, 1H), 4.29-4.23 (m,2H), 1.87-1.84 (m, 2H), 1.10 (s, 6H). mGluR5 PAM EC₅₀: +++. Fold shiftat 1 μM: +++.

Synthesized from 3-methylcyclopentenone, 2-amino-4- bromobenzoic acid,and 2-bromoisonicotinonitrile according to General Experimentals G30,C2, B1, and A1. MS (ESI+): m/z 357 (M + H⁺); ¹H NMR (300 MHz, CD₃OD) δ8.85-8.84 (d, J = 5.19 Hz, 1H), 8.39-8.36 (d, J = 8.37 Hz, 1H),8.11-7.96 (m, 3H), 7.81 (s, 1H), 7.69- 7.60 (m, 2H), 4.22-4.18 (t, J =6.42 Hz, 2H), 3.09 (s, 2H), 2.02-1.98 (t, J = 6.53 Hz, 2H), 1.23 (s,6H). mGluR5 PAM EC₅₀: +.

Synthesized from 3-methylcyclopentenone, 2-amino-4- bromobenzoic acid,and 2-bromoisonicotinonitrile according to General Experimentals G30,C2, B1, and A1, MS (ESI+): m/z 357 (M + H⁺); ¹H NMR (300 MHz, CD₃OD) δ8.85-8.84 (d, J = 4.92 Hz, 1H), 8.38-8.35 (d, J = 8.58 Hz, 1H),8.10-7.96 (m, 3H), 7.81 (s, 1H), 7.69- 7.60 (m, 2H), 3.88 (s, 2H),3.26-3.21 (m, 2H), 1.90-1.86 (t, J = 6.74 Hz, 2H), 1.97 (s, 6H). mGluR5PAM EC₅₀: +.

Synthesized form 3-methylcyclopentenone, 2-amino-4- bormobenzoic acid,and 6-bromonicotinonitrile according to General Experimentals G30, C2,B1, and A1. MS (ESI+): m/z 357 (M + H⁺); ¹H NMR (300 MHz, CD₃OD) δ 9.00(s, 1H), 8.38-8.35 (d, J = 8.40 Hz, 1H), 8.30-8.27 (d, J = 8.22 Hz, 1H),8.10-8.04 (m, 2H), 7.93- 7.90 (d, J = 8.64 Hz, 2H), 7.69-7.64 (d, J =16.03 Hz, 1H), 3.88 (s, 2H), 3.39-3.35 (m, 2H), 1.91-1.87 (t, J = 6.66Hz, 2H), 1.20 (s, 6H).

Synthesized from 3-methylcyclopentenone, 2-amino-4- bromobenzoic acid,and 2-bromo-4-methylthiazole according to General Experimentals G30, C2,B1, and A1. MS (ESI+): m/z 352 (M + H ⁺); ¹H NMR (300 MHz, CDCl₃) δ8.28-8.25 (d, J = 8.34 Hz, 1H), 7.71 (s, 1H), 7.63-7.61 (d, J = 8.43 Hz,1H), 7.54-7.38 (q, 2H), 6.90 (s, 1H), 3.84 (s, 2H), 3.06-3.02 (t, J =7.13 Hz, 2H), 2.51 (s, 3H), 1.79-1.75 (t, J = 7.11 Hz, 2H), 1.22 (s,6H). mGluR5 PAM EC₅₀: ++++.

Synthesized as a mixture of isomers by HCl addition to8,8-dimethyl-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one, which was synthesized from3-methylcyclopentenone, 2-amino-4- bromobenzoic acid, and 2-pyridiylacetylene according to General Experimentals G30, C2, B1, A1. Theisomers were separated by column chromatography. Separated isomer 1: MS(ESI+): m/z 366 (M + H⁺): mGluR5 PAM EC₅₀: +. Separated isomer 2: MS(ESI+): m/z 366 (M + H⁺); mGluR5 PAM EC₅₀: ++. and

Synthesized from isobutyronitrile, 2-amino-4- methoxybenzoic acid, and2-(chloromethyl)pyridine according to General Experimentals C6, B1, G19,and G21.. MS (ES+): m/z 336 (M + H⁺). mGluR5 PAM EC₅₀: +++.

Synthesized from isobutyronitrile, 2-amino-4- methoxybenzoic acid, and1-(pyridin-2-yl)ethanol according to General Experimentals C6, B1, G19,G20, and G21B. MS (ESI+): m/z 350 (M + H⁺).

Synthesized from isobutyronitrile, 2-amino-4- nitrobenzoic acid, andpicolinic acid according to General Experimentals C6, B5, G29 and G28.MS (ESI+): m/z 349 (M + H⁺). mGluR5 PAM EC₅₀: ++.

Synthesized from isobutyronitrile, 2-aminoterephthalic acid, andpyridin-2-amine according to General Experimentals C6, B1 and G28. MS(ESI+): m/z 349 (M + H⁺); ¹H NMR (300 MHz, CD₃OD): δ 8.54-8.50 (m, 3H),8.37 (d, J = 1.2 Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 8.4 Hz,1H), 7.74-7.70 (m, 1H), 3.91 (s, 2H), 3.38-3.33 (t, J = 6.9 Hz, 2H),1.91-1.86 (t, J = 6.9 Hz, 2H), 1.20 (s, 6H). mGluR5 PAM EC₅₀: ++.

Synthesized from isobutyronitrile, 2-aminoterephthalic acid andpyridin-4-amine according to General Exaperimental C6, B1 and G28. MS(ESI+): m/z 349 (M + H⁺); ¹H NMR (300 MHz, DMSO-d₆): δ 8.80 (d, J = 6.9Hz, 2H), 8.44 (d, J = 6.6 Hz, 2H), 8.35 (s, 1H), 8.28 (d, J = 8.4 Hz,1H), 8.08 (d, J = 8.1 Hz, 1H), 3.92 (s, 2H), 3.04-2.99 (t, J = 6.8 Hz,2H), 1.72-1.67 (t, J = 6.8 Hz, 2H), 1.04 (s, 6H).

Synthesized from isobutyronitrile, 2-aminoterephthalic acid andpyridin-3-amine according to General Exaperimental C6, B1 and G28. MS(ESI+): m/z 349 (M + H⁺); ¹H NMR (300 MHz, CD₃OD): δ 9.65 (s, 1H), 8.86(d, J = 8.7 Hz, 1H), 8.68 (d, J = 5.4 Hz, 1H), 8.50 (d, J = 8.4 Hz, 1H),8.34 (s, 1H), 8.29 (d, J = 8.4 Hz, 1H), 8.18-8.13 (dd, J = 8.7, 5.7 Hz,1H), 3.90 (s, 2H), 3.41-3.36 (t, J = 6.9 Hz, 2H), 1.91-1.86 (t, J = 6.9Hz, 2H), 1.20 (s, 6H).

Synthesized from 3-methylcyclopent-2-enone, 2- aminoterephthalic acidand pyridin-2-amine according to General Exaperimental G30, C2, B1 andG28. MS (ESI+): m/z 349 (M + H⁺); ¹H NMR (300 MHz, CD₃OD): δ 8.55-8.52(m, 3H), 8.38 (s, 1H), 8.30 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 9.0 Hz,1H), 7.75-7.70 (m, 1H), 4.23- 4.18 (t, J = 6.3 Hz, 2H), 3.10 (s, 2H),2.02-1.97 (t, J = 6.3 Hz, 2H), 1.23 (s, 6H). mGluR5 PAM EC₅₀: ++. Foldshift at 1 μM: +.

Synthesized from isobutyronitrile, 2-aminoterephthalic acid andN-methylpyridin-2-amine according to General Experimental C6, B1 andG28. MS (ESI+): m/z 363 (M + H⁺); ¹H NMR (300 MHz, CD₃OD): δ 8.32 (d, J= 3.9 Hz, 1H), 8.20 (d, J = 8.1 Hz, 1H), 7.82-7.80 (m, 1H), 7.64 (s,1H), 7.61-7.58 (m, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.31-7.26 (m, 1H),3.82 (s, 2H), 3.59 (s, 3H), 3.31-3.25 (t, J = 6.9 Hz, 2H), 1.86-1.81 (t,J = 6.9 Hz, 2H), 1.16 (s, 6H).

Synthesized from isobutyronitrile, 2-amino-4- nitrobenzoic acid, andnicotinic acid according to General Experimentals C6, B1, G29, G26 andG27. MS (ESI+): m/z 349 (M + H⁺); ¹H NMR (300 MHz, CD₃OD): δ 9.42 (s,1H), 9.03 (m, 2H), 8.66 (d, J = 1.8 Hz, 1H), 8.35 (d, J = 8.7 Hz, 1H),8.18-8.15 (m, 1H), 7.89-7.85 (dd, J = 6.0, 1.8 Hz, 1H), 3.87 (s, 2H),3.36-3.32 (t, J = 6.9 Hz, 2H), 1.89-1.84 (t, J = 6.9 Hz, 2H), 1.19 (s,6H).

Synthesized from isobutyronitrile, 2-amino-4- nitrobenzoic acid, andisonicotinic acid according to General Experimentals C6, B1, G29, G26and G27. MS (ESI+): m/z 349 (M + H⁺); ¹H NMR (300 MHz, CD₃OD): δ 9.09(d, J = 5.4 Hz, 2H), 8.65 (d, J = 1.8 Hz, 1H), 8.53 (d, J = 5.1 Hz, 2H),8.37-8.34 (d, J = 8.7 Hz, 1H), 7.92- 7.88 (dd, J = 8.7, 1.8 Hz, 1H),3.88 (s, 2H), 3.36-3.33 (t, J = 6.9 Hz, 2H), 1.90-1.85 (t, J = 6.9 Hz,2H), 1.19 (s, 6H).

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid, 33%methylamine in ethanol and picolinic acid according to GeneralExperimentals C6, B1, G32, G26 and G27. MS (ESI+): m/z 363 (M + H⁺); ¹HNMR (300 MHz, DMSO-d₆): δ 8.30 (d, J = 4.8 Hz, 1H), 8.00 (d, J = 8.7 Hz,1H), 7.91-7.86 (m, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.55 (s, 1H),7.39-7.34 (m, 2H), 3.68 (s, 2H), 3.48 (s, 3H), 3.11-3.07 (t, J = 6.9 Hz,2H), 1.69- 1.64 (t, J = 6.9 Hz, 2H), 1.04 (s, 6H).

Synthesized from 4,4-dimethylpyrrolidin-2-one, 2- aminoterephthalic acidand pyridin-2-amine according to General Exaperimental B1 and G28. MS(ESI+): m/z 335 (M + H⁺); ¹H NMR (300 MHz, CD₃OD): δ 8.56-8.47 (m, 3H),8.36 (d, J = 1.2 Hz, 1H), 8.25 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 8.4 Hz,1H), 7.76-7.74 (m, 1H), 4.01 (s, 2H), 3.25 (s, 2H), 1.36 (s, 6H). mGluR5PAM EC₅₀: +.

Synthesized from 4,4-dimethylpyrrolidin-2-one, 2- amino-4-nitrobenzoicacid, and picolinic acid to General Experimentals B1, G29, G26 and G27.MS (ESI+): m/z 335 (M + H⁺); ¹H NMR (300 MHz, CD₃OD): δ 8.82 (d, J = 4.5Hz, 1H), 8.71 (s, 1H), 8.40-7.32 (m, 2H), 8.24-8.18 (m, 1H), 8.01-7.98(m, 1H), 7.81-7.77 (m, 1H), 4.13 (s, 2H), 3.42 (s, 2H), 1.40 (s, 6H).mGluR5 PAM EC₅₀: +.

Synthesized from 4-methylcyclohexanone, 2-amino-4- bromobenzoic acid,and 2-bromo-4-methylthiazole according to General Experimentals C2, B1,and A1. MS (ESI+): m/z 352 (M + H⁺); ¹H NMR (300 MHz, CD₃OD): δ8.26-8.23 (d, J = 8.31 Hz, 1H), 7.70 (s, 1H), 7.63-7.61 (d, J = 8.37 Hz,1H), 7.53-7.38 (q, 2H), 6.90 (s, 1H), 5.25-5.12 (m, 1H), 3.64-3.56 (m,1H), 3.11-3.05 (m, 2H), 2.51 (s, 3H), 2.12-2.06 (m, 3H), 1.39 (s, 2H),1.03-1.00 (d, J = 6.60 Hz, 3H).

Synthesized from 4-methylcyclohexanone, 2-amino-4- bromobenzoic acid,and 2-bromoisonicotinonitrile according to General Experimentals C2, B1,and A1. MS (ESI+): m/z 357 (M + H⁺); ¹H NMR (300 MHz, CD₃OD): δ8.85-8.84 (d, J = 5.01 Hz, 1H), 8.38-8.35 (d, J = 8.40 Hz, 1H),8.11-7.96 (m, 3H), 7.84 (s, 1H), 7.69- 7.65 (m, 2H), 5.25-5.18 (m, 1H),3.96-3.83 (m, 1H), 3.51-3.47 (m, 1H), 3.23-3.21 (m, 1H), 2.20-2.03 (m,3H), 1.65-1.61 (m, 1H), 1.22-1.17 (m, 1H), 1.07-1.05 (d, J = 6.45 Hz,3H).

Synthesized from 1,4-dioxaspiro[4,5]decan-8-one, 2- amino-4-bromobenzoicacid, and 2-vinylpyridine according to General Experimentals G9, E2, F2,C2, B1, and A1. Mixture of Example 5.3a and Example 5.3b. MS (ESI+): m/z368 (M + H⁺). and

Synthesized from 1,4-dioxaspiro[4.5]decan-8-one, 2- aminoterephthalicacid, and pyridin-2-amine according to General Exaperimental E2, F2, C2,B1 and G28. MS (ESI+): m/z 371 (M + H⁺); ¹H NMR (300 MHz, DMSO-d₆): δ11.47 (s, 1H), 8.45 (d, J = 3.6 Hz, 1H), 8.27-8.18 (m, 3H), 8.10-8.00(m, 2H), 7.33-7.28 (m, 1H), 4.42-4.38 (m, 2H), 3.18-3.14 (m, 2H),2.36-2.27 (m, 4H). mGluR5 PAM EC₅₀: +.

Synthesized from 1,4-dioxaspiro[4.5]decan-8-one, 2- amino-4-nitrobenzoicacid and picolinic acid according to General Experimentals E2, F2, C2,B1, G29, G26 and G27. MS (ESI+): m/z 371 (M + H⁺); ¹H NMR (300 MHz,DMSO-d₆): δ 11.30 (s, 1H), 8.79 (d, J = 4.5 Hz, 1H), 8.57 (s, 1H),8.22-8.08 (m, 4H), 7.76-7.71 (m, 1H), 4.42- 4.37 (m, 2H), 3.41-3.33 (m,2H), 2.49-2.35 (m, 4H).

Synthesized from isobutyronitrile, 2-amino-4- methoxybenzoic acid, and2-iodopyridine according to General Experimentals C6, B1, G19 and G21.MS (ESI+): 322 (M + H⁺). ¹H NMR (300 MHz, CD₃OD): δ 8.36 (d, J = 8.7 Hz,1H), 8.28-8.27 (m, 1H), 8.03-7.99 (t, J = 7.3 Hz, 1H), 7.51-7.47 (dd, J= 6.0, 2.1 Hz, 1H), 7.42 (s, 1H), 7.35-7.31 (m, 1H), 7.25-7.22 (d, J =8.1 Hz, 1H), 3.88 (s, 2H), 3.29-3.24 (t, J = 6.8 Hz, 2H), 1.89-1.84 (t,J = 6.8 Hz, 2H), 1.19 (s, 6H).

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid, andpyridin-2-amine according to General Experimentals C6, B1 and G32. MS(ESI+): 321 (M + H⁺); ¹H NMR (300 MHz, CD₃OD): δ 8.35-8.23 (m, 3H),7.99-7.93 (t, J = 8.4 Hz, 1H), 7.60-7.56 (dd, J = 8.7, 2.1 Hz, 1H), 7.24(d, J = 8.4 Hz, 1H), 7.18-7.13 (m, 1H), 3.86 (s, 2H), 3.27-3.21 (t, J =6.9 Hz, 2H), 1.88- 1.83 (t, J = 6.9 Hz, 2H), 1.18 (s, 6H). mGluR5 PAMEC₅₀: +.

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid, and2-(prop-1-en-2-yl)pyridine according to General Experimentals C6, B1, A1and G33. MS (ESI+): 348 (M + H⁺); ¹H NMR (300 MHz, CDCl₃): δ 8.58 (d, J= 4.1 Hz, 1H), 8.11 (d, J = 8.1 Hz, 1H), 7.54-7.51 (m, 1H), 7.38 (s,1H), 7.17-7.11 (m, 2H), 7.03 (d, J = 7.8 Hz, 1H), 3.81 (s, 2H),3.28-3.24 (m, 2H), 3.05-2.98 (m, 3H), 1.77-1.72 (t, J = 7.0 Hz, 2H),1.33 (d, J = 6.5 Hz, 3H), 1.10 (s, 6H).

Synthesized from isobutyronitrile, dimethyl 2- aminoterephthalate,sodium acetate, 2-chloropyridine and 18-crown-6-according to GeneralExperimentals G31, C6, B1, G1, G2 and G21. MS (ESI+): m/z 336 (M + H⁺);¹H NMR (300 MHz, CD₃OD): δ 8.33 (d, J = 8.3 Hz, 1H), 8.26-8.24 (m, 1H),8.08-8.02 (td, J = 8.1, 1.8 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.79 (s,1H), 7.27- 7.20 (m, 2H), 5.71 (s, 2H), 3.87 (s, 2H), 3.34-3.29 (t, J =6.9 Hz, 2H), 1.89-1.84 (t, J = 6.9 Hz, 2H), 1.18 (s, 6H). mGluR5 PAMEC₅₀: ++.

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid and2-(prop-1-en-2-yl)pyridine according to General Experimentals C6, B1 andA1. MS (ESI+): 346 (M + H⁺); ¹H NMR (300 MHz, CD₃OD): δ 8.86-8.83 (dd, J= 6.0, 1.0 Hz, 1H), 8.73-8.67 (td, J = 8.1, 1.5 Hz, 1H), 8.45-8.40 (m,2H), 8.11-8.06 (m, 1H), 7.90-7.86 (m, 2H), 7.64 (s, 1H), 3.85 (s, 2H),3.41-3.36 (t, J = 6.8 Hz, 2H), 2.53 (d, J = 1.20 Hz, 3H), 1.92-1.87 (t,J = 6.8 Hz, 2H), 1.20 (s, 6H). mGluR5 PAM EC₅₀: ++.

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid and2-vinylpyridine according to General Experimentals C6, B1, A1 and G23.MS (ESI+): 346 (M + H⁺); ¹H NMR (300 MHz, CD₃OD): δ 8.70 (d, J = 5.1 Hz,1H), 8.55-8.50 (t, J = 8.1 Hz, 1H), 8.30 (d, J = 8.7 Hz, 1H), 7.93-7.90(m, 2H), 7.62-7.59 (m, 2H), 3.87 (s, 2H), 3.32-3.27 (t, J = 6.9 Hz, 2H),3.10- 3.03 (m, 1H), 2.90-2.88 (m, 1H), 2.17-2.10 (m, 2H), 1.89-1.84 (t,J = 6.9 Hz, 2H), 1.18 (s, 6H).

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid and2-ethynylpyridine according to General Experimentals C6, B1, A1 and G34.MS (ESI+): 348 (M + H⁺). ¹H NMR (300 MHz, CD₃OD): δ 8.96 (d, J = 5.8 Hz,1H), 8.69-8.67 (m, 1H), 8.56-8.53 (m, 1H), 8.40-8.37 (m, 2H), 8.15-8.06(m, 2H), 3.91- 3.88 (s, 2H), 3.38-3.33 (t, J = 6.6 Hz, 2H), 1.92-1.87(t, J = 6.6 Hz, 2H), 1.20 (s, 6H). Note: The protons of COCH₂ exchangedwith deuterium in the NMR sample. mGluR5 PAM EC₅₀: +++.

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid,2-ethynylpyridine and MeI according to General Experimentals C6, B1, A1,G34 and G9. MS (ESI+): 362 (M + H⁺); ¹H NMR (300 MHz, DMSO-d₆): δ 8.54(d, J = 4.4 Hz, 1H), 8.19-8.16 (m, 2H), 8.04-7.93 (m, 2H), 7.71-7.68 (d,J = 8.1 Hz, 1H), 7.44-7.41 (m, 1H), 5.33-5.31 (m, 1H), 3.73 (s, 2H),3.02- 2.97 (t, J = 7.0 Hz, 2H), 1.69-1.64 (t, J = 7.0 Hz, 2H), 1.53-1.51(d, J = 6.8 Hz, 3H), 1.02 (s, 6H).

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid and2-ethynylpyridine according to General Experimentals C6, B1, A1, G34 andG8. Converted to HCl salt. MS (ESI+): 398, 401 (M + H⁺); ¹H NMR (300MHz, D₂O): δ 8.62 (d, J = 5.5 Hz, 1H), 8.33-8.28 (m, 1H), 8.23 (d, J =8.4 Hz, 1H), 7.90-7.87 (m, 1H), 7.84-7.80 (m, 1H), 7.73-7.70 (m, 2H),5.69 (s, 1H), 3.80 (s, 2H), 3.27-3.22 (t, J = 6.7 Hz, 2H), 1.80- 1.75(t, J = 6.7 Hz, 2H), 1.56 (s, 3H), 1.06 (s, 6H).

Synthesized from isobutyronitrile, dimethyl 2- aminoterephthalate,2-ethynylpyridine and 6M HCl according to General Experimentals G31, C6,B1, G1, G2, G16, G38, G33, G14 and G33. MS (ESI+): 348 (M + H⁺); ¹H NMR(300 MHz, CD₃OD) δ 8.77-8.75 (d, J = 5.58 Hz, 1H), 8.61-8.55 (t, J =7.65 Hz, 1H), 8.28-8.25 (d, J = 8.10 Hz, 1H), 8.07-8.05 (d, J = 8.01 Hz,1H), 7.98-7.94 (t, J = 6.60 Hz, 1H), 7.68-7.65 (m, 2H), 3.86 (s, 2H),3.38-3.36 (m, 2H), 3.23-3.18 (t, J = 7.50 Hz, 2H), 3.05-3.00 (t, J =7.80 Hz, 2H), 2.31-2.21 (m, 2H), 1.90-1.85 (t, J = 6.54 Hz, 2H), 1.18(s, 6H).

Synthesized from isobutyronitrile, dimethyl 2- aminoterephthalate andpyridin-2-ylmethanol according to General Experimentals G31, C6, B1 andG21. MS (ESI+): 350 (M + H⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.86-8.84 (d, J= 6.03 Hz, 1H), 8.67-8.61 (td, J = 7.91, 1.45 Hz, 1H), 8.37-8.34 (d, J =8.61 Hz, 1H), 8.14-8.11 (d, J = 7.98 Hz, 1H), 8.07-8.03 (t, J = 6.90 Hz,1H), 7.81-7.79 (m, 2H), 5.11 (s, 2H), 5.03 (s, 2H), 3.88 (s, 2H),3.35-3.34 (m, 2H), 1.89-1.84 (t, J = 6.82 Hz, 2H), 1.18 (s, 6H).

Synthesized from isobutyronitrile, 2-amino-4- nitrobenzoic acid,picolinic acid and sodium azide according to General Experimentals C6,B1, G29 and H17. MS (ESI+): m/z 364 (M + H⁺); ¹H NMR (300 MHz, DMSO-d₆):δ 11.33 (s, 1H), 9.99 (s, 1H), 8.32 (d, J = 4.1 Hz, 1H), 8.23 (s, 1H),8.15 (d, J = 8.7 Hz, 1H), 7.89- 7.83 (td, J = 8.1, 1.8 Hz, 1H),7.70-7.60 (m, 2H), 7.14- 7.10 (m, 1H), 3.71 (s, 2H), 3.21-3.16 (t, J =6.9 Hz, 2H), 1.73-1.68 (t, J = 6.9 Hz, 2H), 1.08 (s, 6H). mGluR5 PAMEC₅₀: +.

Synthesized from isobutyronitrile, dimethyl 2- aminoterephthalate and2-ethynylpyridine according to General Experimentals G31, C6, B1, G1,G2, G16 and G38. MS (ESI+): 360 (M + H⁺); ¹H NMR (300 MHz, CDCl₃) δ8.56-8.55 (d, J = 3.27 Hz, 1H), 8.21-8.18 (d, J = 8.25 Hz, 1H), 7.95 (s,1H), 7.68-7.60 (m, 2H), 7.42- 7.39 (d, J = 7.68 Hz, 1H), 7.24-7.20 (m,1H), 5.89 (s, 1H), 3.78 (s, 2H), 3.02-2.97 (t, J = 7.01 Hz, 2H), 1.72-1.67 (t, J = 6.99 Hz, 2H), 1.07 (s, 6H).

Synthesized from isobutyronitrile, dimethyl 2- aminoterephthalate and2-ethynylpyridine according to General Experimentals G31, C6, B1, G1,G2, G16, G38 and E1. MS (ESI+): 362 (M + H⁺); ¹H NMR (300 MHz, CDCl₃) δ8.62 (s, 1H), 8.35-8.32 (d, J = 8.25 Hz, 1H), 7.86 (s, 1H), 7.72-7.65(m, 2H), 7.54-7.51 (d, J = 7.62 Hz, 1H), 7.32-7.30 (d, J = 6.24 Hz, 1H),6.51-6.35 (d, J = 59.40 Hz, 1H), 3.84 (s, 2H), 3.06-3.01 (t, J = 7.10Hz, 2H), 1.78-1.74 (t, J = 7.07 Hz, 2H), 1.11 (s, 6H).

Synthesized from 4,4-dimethypyrrolidin-2-one, 2-amino-4-(methoxycarbonyl)benzoic acid and picolinoyl choride accordingto General Experimentals C1 and H6. MS (ESI+): m/z 378 (M + H⁺); ¹H NMR(300 MHz, CDCl₃) δ 8.64 (d, J = 4.1 Hz, 1H), 8.38 (d, J = 8.3 Hz, 1H),8.22-8.20 (m, 2H), 7.96-7.87 (m, 2H), 7.53-7.49 (m, 1H), 4.00 (s, 2H),3.00 (s, 2H), 1.29 (s, 6H).

Synthesized from 5-methylazepan-2-one, 2-amino-4-(methoxycarbonyl)benzoic acid and picolinoyl chloride according toGeneral Experimentals C1 and H6. MS (ESI+): m/z 392 (M + H⁺); ¹H NMR(300 MHz, CDCl₃) δ 8.64 (d, J = 4.3 Hz, 1H), 8.36 (d, J = 8.2 Hz, 1H),8.20 (d, J = 7.7 Hz, 1H), 8.13 (s, 1H), 7.95-7.88 (m, 2H), 7.53-7.49 (m,1H), 5.22-5.16 (dd, J = 14.0, 6.7 Hz, 1H), 3.68-3.59 (m, 1H), 3.17-3.07(m, 2H), 2.32-2.10 (m, 5H), 1.03 (d, J = 6.6 Hz, 3H).

Synthesized from isobutyronitrile, 2-amino-4- bromobenzonic acid,tert-butyl 3-oxopyrrolidine-1- carboxylate, bis(pinacolato)diboron and2-bromobenzene according to General Experimentals C6, B1, A8, A4, F3 andG32. MS (ESI+): m/z 372 (M + H⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.26 (d, J =8.9 Hz, 1H), 7.63-7.61 (m, 2H), 7.34-7.29 (t, J = 7.8 Hz, 2H), 6.78-6.73(t, J = 7.3 Hz, 1H), 6.63 (d, J = 8.0 Hz, 2H), 6.56 (s, 1H), 4.58-4.55(m, 2H), 4.41-4.31 (m, 2H), 3.84 (s, 2H), 3.07-3.02 (t, J = 7.1 Hz, 2H)1.80-1.75 (t, J = 7.1 Hz, 2H), 1.13 (s, 6H).

Synthesized from isobutyronitrile, 2-amino-4- bromobenzonic acid,tert-butyl 3-oxopyrrolidine-1- carboxylate, bis(pinacolato)diboron and2- bromopyridine according to General Experimentals C6, B1, A8, A4, F3and G32. MS (ESI+): m/z 373 (M + H⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.38 (d,J = 8.4 Hz, 1H), 8.16-8.11 (t, J = 7.4 Hz, 1H), 8.06-7.99 (m, 2H), 7.82(s, 1H), 7.33-7.30 (m, 1H), 7.10-7.05 (t, J = 6.6 Hz, 1H), 6.96 (s, 1H),4.99 (s, 2H), 4.75 (s, 2H), 3.89 (s, 2H), 3.42-3.37 (t, J = 6.8 Hz, 2H),1.91-1.87 (t, J = 6.8 Hz, 2H), 1.20 (s, 6H).

Synthesized from isobutyronitrile, 2-amino-4- bromobenzonic acid,tert-butyl 3-oxopyrrolidine-1- carboxylate, bis(pinacolato)diboron and1-bromo-3- fluorobenzene according to General Experimentals C6, B1, A8,A4, F3 and G32. MS (ESI+): m/z 390 (M + H⁺); ¹H NMR (300 MHz, CDCl₃) δ8.27 (d, J = 8.8 Hz, 1H), 7.62-7.60 (m, 2H), 7.24-7.19 (m, 1H),6.56-6.55 (m, 1H), 6.47-6.28 (m, 3H), 4.56-4.54 (m, 2H), 4.36-4.35 (m,2H), 3.85 (s, 2H), 3.07-3.02 (t, J = 7.1 Hz, 2H) 1.80- 1.75 (t, J = 7.1Hz, 2H), 1.13 (s, 6H).

Synthesized from isobutyronitrile, 2-amino-4- bromobenzonic acid,tert-butyl piperazin-1-carboxylate and 2-bromopyridine according toGeneral Experimentals C6, B1, G32, F3 and G32. MS (ESI+): m/z 390 (M +H⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.17-8.09 (m, 2H), 8.02 (d, J = 6.3 Hz,1H), 7.43 (d, J = 9.3 Hz, 1H), 7.33-7.29 (dd, J = 9.2, 2.3 Hz, 1H),7.10-7.05 (t, J = 6.7 Hz, 1H), 6.85 (s, 1H), 4.04- 4.01 (m, 4H),3.93-3.90 (m, 4H), 3.83 (s, 2H), 3.31-3.27 (m, 2H), 1.87-1.83 (t, J =6.8 Hz, 2H), 1.17 (s, 6H).

Synthesized from isobutyronitrile, 2-aminoterephthalic acid, HBr salt of2-bromo-1-(pyridin-2-yl)ethanone and CH₃COONH₄ according to GeneralExperimentals C6, B1 and H13. MS (ESI+): 372 (M + H⁺); ¹H NMR (300 MHz,CD₃OD): δ 8.71 (d, J = 5.8 Hz, 1H), 8.57-8.43 (m, 4H), 8.39-8.32 (m,2H), 7.88-7.83 (t, J = 7.2 Hz, 1H), 3.90 (s, 2H), 3.37-3.32 (t, J = 6.9Hz, 2H), 1.90-1.85 (t, J = 6.9 Hz, 2H), 1.19 (s, 6H). mGluR5 PAM EC₅₀:+.

Synthesized from isobutyronitrile, 2-amino-4- bromobenzonic acid,bis(pinacolato)diboron, 2- bromopyridine and 4-bromo-1H-imidazoleaccording to General Experimentals G32, C6, B1 and A4. MS (ESI+): 372(M + H⁺); ¹H NMR (300 MHz, CD₃OD): δ 8.86 (s, 1H), 8.66 (s, 1H), 8.58(d, J = 3.9 Hz, 1H), 8.30 (d, J = 9.0 Hz, 1H), 8.09-8.03 (m, 3H),7.86-7.83 (d, J = 8.1 Hz, 1H), 7.48-7.44 (m, 1H), 3.88 (s, 2H),3.23-3.18 (t, J = 6.9 Hz, 2H), 1.87-1.82 (t, J = 6.9 Hz, 2H), 1.16 (s,6H).

Synthesized from isobutyronitrile, 2-amino-4- bromobenzonic acid, ,picolinaldehyde and TosMIC according to General Experimentals H13, C6,B1 and G32. MS (ESI+): m/z 372 (M + H⁺); ¹H NMR (300 MHz, CD₃OD): δ 9.01(s, 1H), 8.40 (s, 1H), 8.30 (d, J = 8.7 Hz, 1H), 7.99 (s, 1H), 7.90-7.83(td, J = 7.7, 1.8, 1H), 7.63-7.61 (m, 2H), 7.48-7.44 (dd, J = 8.7, 1.8Hz, 1H), 7.39-7.34 (m, 1H), 3.87 (s, 2H), 3.07-3.02 (t, J = 6.9 Hz, 2H),1.82-1.77 (t, J = 6.9 Hz, 2H), 1.12 (s, 6H).

Synthesized from dimethyl 2-aminoterephthalate, isobutyonitrile,2-ethynylpyridine and according to General Experimentals G31, C6, B1,G1, G2, G16 and H16. MS (ESI+): m/z 373 (M + H⁺); ¹H NMR (300 MHz,CD₃OD): δ 8.89 (d, J = 5.4 Hz, 1H), 8.51 (d, J = 8.7 Hz, 1H), 8.45-8.42(m, 2H), 8.34-8.32 (m, 2H), 8.00 (s, 1H), 7.89-7.85 (m, 1H), 3.91 (s,2H), 3.42-3.37 (t, J = 6.6 Hz, 2H), 1.93-1.88 (t, J = 6.6 Hz, 2H), 1.19(s, 6H).

Synthesized from isobutyronitrile, 2-amino-4- bromobenzonic acid, ,picolinaldehyde, TosMIC and chlorotributylstannane tributyltin chorideaccording to General Experimentals H12, G37, C6, B1 and A5. MS (ESI+):m/z 373 (M + H⁺); ¹H NMR (300 MHz, CD₃OD): δ 8.81 (d, J = 5.7 Hz, 1H),8.53-8.49 (m, 3H), 8.39-8.27 (m, 3H), 7.80-7.76 (t, J = 6.3 Hz, 1H),3.91 (s, 2H), 3.41- 3.36 (t, J = 6.9 Hz, 2H), 1.93-1.88 (t, J = 6.9 Hz,2H), 1.21 (s, 6H). mGluR5 PAM EC₅₀: ++.

Synthesized from isobutyronitrile, 2-amino-4- bromobenzonic acid,bis(pinacolato)diboron, picolinaldehyde and 2-aminoethanol according toGeneral Experimentals H11, C6, B1 and A4. MS (ESI+): m/z 373 (M + H⁺);¹H NMR (300 MHz, CD₃OD): δ 8.84 (brs, 1H), 8.46-8.44 (m, 2H), 8.30-8.24(m, 4H), 7.80-7.76 (m, 1H), 3.90 (s, 2H), 3.40-3.35 (t, J = 6.9 Hz, 2H),1.92-1.87 (t, J = 6.9 Hz, 2H), 1.18 (s, 6H).

Synthesized from isobutyronitrile, 2-amino-4- bromobenzonic acid,bis(pinacolato)diboron, 2- bromothiazole and 2-iodopyridine according toGeneral Experimentals C6, B1, A4 and A7. MS (ESI+): m/z 389 (M + H⁺); ¹HNMR (300 MHz, DMSO-d₆): δ 8.73 (s, 1H), 8.63 (d, J = 4.5 Hz, 1H),8.28-8.22 (m, 2H), 8.15-8.10 (m, 2H), 7.97-7.92 (t, J = 8.1 Hz, 1H),7.42-7.37 (m, 1H), 3.76 (s, 2H), 3.10-3.05 (t, J = 6.9 Hz, 2H),1.73-1.68 (t, J = 6.9 Hz, 2H), 1.06 (s, 6H).

Synthesized from isobutyronitrile, 2-amino-4- bromobenzonic acid,bis(pinacolato)diboron, 5- bromothiazole and 2-iodopyridine according toGeneral Experimentals C6, B1, A4 and A7. MS (ESI+): m/z 389 (M + H⁺); ¹HNMR (300 MHz, DMSO-d₆): δ 8.68 (d, J = 4.8 Hz, 1H), 8.63 (s, 1H),8.19-8.16 (m, 2H), 8.03-7.88 (m, 3H), 7.56-7.52 (m, 1H), 3.76 (s, 2H),3.03-2.97 (t, J = 6.9 Hz, 2H), 1.72-1.67 (t, J = 6.9 Hz, 2H), 1.03 (s,6H). mGluR5 PAM EC₅₀: +.

Synthesized from isobutyronitrile, 2-amino-4- bromobenzonic acid,bis(pinacolato)diboron and 2- bromo-1-(pyridin-2-yl)ethanone accordingto General Experimentals H10, C6, B1 and A4. MS (ESI+): m/z 389 (M +H⁺); ¹H NMR (300 MHz, CD₃OD): δ 9.01 (s, 1H), 8.89 (d, J = 5.5 Hz, 1H),8.74-8.68 (m, 2H), 8.51- 8.44 (m, 3H), 8.10-8.05 (m, 1H), 3.91 (s, 2H),3.41-3.36 (t, J = 6.9 Hz, 2H), 1.92-1.87 (t, J = 6.9 Hz, 2H), 1.20 (s,6H).

Synthesized as a mixture from isobutyronitrile, 2-amino- 4-bromobenzonicacid ethynyltrimethylsilane and chlorobenzene according to GeneralExperimentals C6, B1, A2, G36 and H9. MS (ESI+): m/z 372 (M + H⁺); ¹HNMR (300 MHz, DMSO-d₆): δ 9.57 (s, 1H), 8.29-8.23 (m, 2H), 8.13-8.09 (m,1H), 7.99-7.96 (m, 2H), 7.69- 7.64 (t, J = 7.8 Hz, 2H), 7.58-.55 (m,1H), 3.77-3.75 (m, 2H), 3.09-3.04 (m, 2H), 1.74-1.68 (m, 2H), 1.06- 1.03(m, 6H).

Synthesized from isobutyronitrile, 2-aminoterephthalic acid andpicolinonitrile according to General Experimentals C6, B1, G35 and H8.MS (ESI+): 374 (M + H⁺); ¹H NMR (300 MHz, CD₃OD): δ 8.91-8.89 (d, J =5.0 Hz, 1H), 8.62-8.51 (m, 4H), 8.41-8.35 (m, 1H), 7.93-7.88 (m, 1H),3.92 (s, 2H), 3.42-3.37 (t, J = 6.7 Hz, 2H), 1.93-1.88 (t, J = 6.7 Hz,2H), 1.21 (s, 6H).

Synthesized from 4,4-dimethylpyrrolidin-2-one, 2-amino-4-(methoxycarbonyl)benzoic acid and picolinyl chloride accordingto General Experimentals B1 and H6. MS (ESI+): 360 (M + H⁺); ¹H NMR (300MHz, CD₃OD): δ 8.86 (brs, 1H), 8.53-8.41 (m, 4H), 8.19-8.14 (t, J = 8.4Hz, 1H), 7.73 (s, 1H), 4.09 (s, 2H), 3.24 (s, 2H), 1.33 (s, 6H).

Synthesized from piperidin-2-one, 2-amino-4- (methoxycarbonyl)benzoicacid and picolinyl chloride according to General Experimentals B1 andH6. MS (ESI+): m/z 346 (M + H⁺); ¹H NMR (300 MHz, CD₃OD): δ 8.85 (d, J =4.8 Hz, 1H), 8.60-8.40 (m, 4H), 8.19-8.16 (t, J = 6.3 Hz, 1H), 7.75-7.71(m, 1H), 4.19- 4.15 (t, J = 5.9 Hz, 2H), 3.55-3.51 (t, J = 5.9 Hz, 2H),2.24-2.06 (m, 4H).

Synthesized from isobutyronitrile, 2-amino-4- (methoxycarbonyl)benzoicacid and picolinoyl chloride according to General Experimentals B1 andH6. MS (ESI+): m/z 374 (M + H⁺); ¹H NMR (300 MHz, CD₃OD): δ 8.86 (d, J =4.9 Hz, 1H), 8.59-8.42 (m, 4H), 8.20-8.14 (td, J = 7.8, 1.6 Hz, 1H),7.76-7.72 (m, 1H), 3.92 (s, 2H), 3.42-3.37 (t, J = 6.8 Hz, 2H),1.93-1.89 (t, J = 6.8 Hz, 2H), 1.22 (s, 6H). mGluR5 PAM EC₅₀: ++.

Synthesized from azepan-2-one, 2-amino-4- (methoxycarbonyl)benzoic acidand picolinoyl chloride according to General Experimentals B1 and H6. MS(ESI+): m/z 360 (M + H⁺); ¹H NMR (300 MHz, CD₃OD): δ 8.88 (brs, 1H),8.60-8.45 (m, 4H), 8.21-8.16 (t, J = 7.8 Hz, 1H), 7.76 (brs, 1H),4.61-4.58 (m, 2H), 3.55-3.52 (m, 2H), 2.58-1.92 (m, 6H).

Synthesized from 5-methylazepan-2-one, 2-amino-4-(methoxycarbonyl)benzoic acid and picolinoyl chloride according toGeneral Experimentals B1 and H6. MS (ESI+): m/z 374 (M + H⁺); ¹H NMR(300 MHz, CD₃OD): δ 8.58 (brs, 1H), 8.55-8.46 (m, 4H), 8.23-8.18 (t, J =7.8 Hz, 1H), 7.78 (s, 1H), 5.25-5.18 (dd, J = 14.7, 6.0 Hz, 1H),4.00-3.91 (m, 1H), 3.57-3.49 (m, 1H), 2.26- 2.10 (m, 3H), 1.64-1.60 (m,1H), 1.45-1.31 (m, 2H), 1.07 (d, J = 7.5 Hz, 3H).

Synthesized from isobutyronitrile, 2-amino-4- (methoxycarbonyl)benzoicacid, picolinoyl chloride and P₂S₅ according to General Experimentals H6and H7. MS (ESI+): m/z 390 (M + H⁺); ¹H NMR (300 MHz, CD₃OD): δ 8.77 (d,J = 4.8 Hz, 1H), 8.36-8.27 (m, 3H), 8.20-8.06 (m, 2H), 7.66-7.62 (m,1H), 3.80 (s, 2H), 3.07- 3.03 (t, J = 6.8 Hz, 2H), 1.73-1.68 (t, J = 6.8Hz, 2H), 1.05 (s, 6H). mGluR5 PAM EC₅₀: ++.

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid,bis(pinacolato)diboron and 2-(4- bromophenyl)pyridine according toGeneral Experimentals C6, B1 and A4. MS (ESI+): m/z 382 (M + H⁺); ¹H NMR(300 MHz, CD₃OD): δ 8.91 (d, J = 4.9 Hz, 1H), 8.76-8.70 (td, J = 7.8,1.5 Hz, 1H), 8.51- 8.47 (t, J = 5.1 Hz, 2H), 8.21-8.07 (m, 6H), 8.01 (d,J = 1.4 Hz, 1H), 3.92 (s, 2H), 3.41-3.36 (t, J = 6.9 Hz, 2H), 1.93-1.88(t, J = 6.9 Hz, 2H), 1.21 (s, 6H).

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid,bis(pinacolato)diboron, 6- bromopyridin-3-ylboronic acid and2-iodopyridine according to General Experimentals C6, B1 and A4. MS(ESI+): m/z 383 (M + H⁺); ¹H NMR (300 MHz, CD₃OD): δ 9.37 (d, J = 1.9Hz, 1H), 8.99 (d, J = 5.8 Hz, 1H), 8.80-8.74 (td, J = 7.9, 1.5 Hz, 1H),8.67-8.47 (m, 6H), 8.18-8.13 (m, 1H), 3.92 (s, 2H), 3.41-3.36 (t, J =6.9 Hz, 2H), 1.93-1.88 (t, J = 6.9 Hz, 2H), 1.21 (s, 6H).

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid,bis(pinacolato)diboron, 5-bromo-2- chloropyridine and2-(tributylstannyl)pyridine according to General Experimentals C6, B1,A4 and A5. MS (ESI+): m/z 383 (M + H⁺); ¹H NMR (300 MHz, CD₃OD): δ 9.35(s, 1H), 8.96 (d, J = 5.4 Hz, 1H), 8.90 (d, J = 8.4 Hz, 1H), 8.81-8.75(t, J = 7.5 Hz, 1H), 8.70-8.62 (m, 2H), 8.53 (d, J = 8.4 Hz, 1H),8.21-8.13 (m, 3H), 3.92 (s, 2H), 3.41-3.36 (t, J = 6.9 Hz, 2H),1.93-1.88 (t, J = 6.9 Hz, 2H), 1.21 (s, 6H).

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid,bis(pinacolato)diboron, pyridin-2- ylzinc(II) bromide and2-chloro-5-iodopyrimidine according to General Experimentals C6, B1, A6and A4. MS (ESI+): m/z 384 (M + H⁺); ¹H NMR (300 MHz, DMSO-d₆): δ 9.67(s, 2H), 8.91 (s, 1H), 8.80 (d, J = 4.2 Hz, 1H), 8.68-8.65 (dd, J = 8.4,1.3 Hz, 1H), 8.39-8.36 (d, J = 8.5 Hz, 1H), 8.26 (d, J = 7.9 Hz, 1H),8.09-8.03 (td, J = 7.8, 1.6 Hz, 1H), 7.57-7.54 (m, 1H), 3.77 (s, 2H),3.29-3.24 (t, J = 6.9 Hz, 2H), 1.77-1.72 (t, J = 6.9 Hz, 2H), 1.09 (s,6H). mGluR5 PAM EC₅₀: +.

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid,3-chloro-6-iodopyridazine and 2- (tributylstannyl)pyridine according toGeneral Experimentals C6, B1, A4 and A5. MS (ESI+): m/z 384 (M + H⁺); ¹HNMR (300 MHz, CD₃OD): δ 8.99 (d, J = 5.4 Hz, 1H), 8.90-8.84 (m, 2H),8.72-8.67 (m, 3H), 8.57 (s, 2H), 8.14-8.12 (m, 1H), 3.93 (s, 2H),3.43-3.38 (t, J = 6.9 Hz, 2H), 1.94-1.89 (t, J = 6.9 Hz, 2H), 1.22 (s,6H).

Synthesized from isobutyronitrile, 2-amino-4- bromobenzoic acid,5-bromo-2-chloropyrimidine and 2- (tributylstannyl)pyridine according toGeneral Experimentals C6, B1, A4 and A5. MS (ESI+): m/z 384 (M + H⁺); ¹HNMR (300 MHz, DMSO-d₆): δ 9.67 (s, 2H), 8.91 (s, 1H), 8.80 (d, J = 4.2Hz, 1H), 8.68-8.65 (dd, J = 8.4, 1.3 Hz, 1H), 8.39-8.36 (d, J = 8.5 Hz,1H), 8.26 (d, J = 7.9 Hz, 1H), 8.09-8.03 (td, J = 7.8, 1.6 Hz, 1H),7.57- 7.54 (m, 1H), 3.77 (s, 2H), 3.29-3.24 (t, J = 6.9 Hz, 2H),1.77-1.72 (t, J = 6.9 Hz, 2H), 1.09 (s, 6H).

Example S. General Method for Separation of Isomers

Chiral separations of enantiomers from racemic compounds were performedon chiral columns with isocratic Supercritical Fluid Chromatography(SFC) technology. The chiral columns used for preparative separationswere chosen from 3.0×25.0 cm RegisPack®, or 3.0×25.0 cm (S,S) Whelk-O1columns, both from Regis Technologies, Morton Grove, Ill., or 2.1×25.0cm LUX Cellulose 2 column from Phenomenex, Torrance, Calif., or 3.0×25.0cm 2-Ethylpyridine from Princeton Chromatography, Cranbury, N.J., or2.0×25 cm Pyridyl Amide from ES Industries, West Berlin, N.J. The chiralcolumns used for analytical separations were chosen from 4.6×100 mmRegisPack® or 4.6×100 mm (S,S) Whelk-O1 columns, both from RegisTechnologies, Morton Grove, Ill., or 4.6×100 mm LUX Cellulose 2 columnfrom Phenomenex, Torrance, Calif., or 4.6×100 mm Pyridyl Amide from ESIndustries, West Berlin, N.J. The supercritical fluid (SF) was carbondioxide (CO₂). The co-solvent used with CO₂ was a mixture of isopropanolor acetonitrile with or without methanol, and sometimes, with a smallpercentage of isopropylamine. For a compound separated from preparativecolumn, the first peak (faster moving) was labeled as fraction 1, andthe second peak (slower moving) was labeled as fraction 2. Theenantiomeric purity of each fraction was analyzed on analytical columnsand the retention time (Rt) and the percentage of enantiomeric excess (%ee) were recorded. Unless otherwise indicated, the absolute chemistry ofthe enantiomers was assigned arbitrarily.

Example PS. General Preparative Separation Method

Preparative Separation Method PS(I):

Column: 3.0×25.0 cm RegisPack®. CO₂ co-solvent: isopropanol with 10-90%methanol and 0.1-1% isopropylamine. Isocratic method: 20-70% co-solventat 50-80 mL/min. System pressure: 100-150 bar. Column temperature: 25°C.

Preparative Separation Method PS(II):

Column: 3.0×25.0 cm RegisPack®. CO₂ co-solvent: isopropanol with 0.1-1%isopropylamine. Isocratic method: 20-50% co-solvent at 50-80 mL/min.System pressure 100-150 bar. Column temperature: 25° C.

Preparative Separation Method PS(III):

Column: 3.0×25.0 cm (S,S) Whelk-O1 Regis Pack. CO₂ co-solvent:isopropanol with 25-50% methanol with 0-1% isopropylamine. Isocraticmethod: 20-50% co-solvent at 50-80 mL/min. System pressure: 100-150 bar.Column temperature: 25° C.

Preparative Separation Method PS(IV):

Column: 3.0×25.0 cm (S,S) Whelk-O11 Regis Pack. CO₂ co-solvent:isopropanol with 0.5-1% isopropylamine. Isocratic method: 20-50%co-solvent at 50-80 mL/min. System pressure: 100-150 bar. Columntemperature: 25° C.

Preparative Separation Method PS(V):

Column: 2.1×25.0 cm LUX Cellulose 2 from Phenomenex, Torrance, Calif.CO₂ co-solvent: methanol with 0.5-1% isopropylamine. Isocratic method:20-50% co-solvent at 50-80 mL/min. System pressure: 100-150 bar. Columntemperature: 25° C.

Preparative Separation Method PS(VI)):

Column: 2.1×25.0 cm LUX Cellulose 2 from Phenomenex, Torrance, Calif.CO₂ co-solvent: acetonitrile with 10-25% methanol and 0.1-1%isopropylamine. Isocratic method: 20-60% co-solvent at 50-80 mL/min.System pressure: 100-150 bar. Column temperature: 25° C.

Preparative Separation Method PS(VII):

Column: 3.0×25.0 cm 2-Ethylpyridine from Princeton Chromatography.Cranbury, N.J. CO₂ co-solvent: isopropanol with 0.1-1% isopropylamine.Isocratic method: 20% co-solvent at 80 mL/min. System pressure 100-bar.Column temperature: 25° C.

Preparative Separation Method PS(VIII):

Column: 2.0×25 cm Pyridyl Amide from ES Industries, West Berlin, N.J.CO₂ co-solvent: isopropanol with 10-90% methanol and 0.1-1%isopropylamine. Isocratic method: 10% co-solvent at 80 mL/min. Systempressure: 100-150 bar. Column temperature: 25° C.

Preparative Separation Method PS(IX):

Column: 3.0×25.0 cm RegisPack®. CO₂ co-solvent: ethanol. Isocraticmethod: 30% co-solvent at 80 mL/min. System pressure: 100 bar. Columntemperature: 25° C.

Example AS. General Analytical Separation Method

Analytical Separation Method AS(I):

Column: 4.6×100 mm RegisPack®. CO₂ co-solvent: isopropanol with 10-90%methanol and 0.1-0.5% isopropylamine. Isocratic method: 20-70%co-solvent at 4 mL/min. System Pressure 70-150 bar. Column Temperature:25° C.

Analytical Separation Method AS(II):

Column: 4.6×100 mm RegisPack®). CO₂ co-solvent: isopropanol with 0.1-1%isopropylamine. Isocratic method: 20-50% co-solvent at 50-80 mL/min.System pressure 70-150 bar. Column temperature: 25° C.

Analytical Separation Method AS(III):

Column: 4.6×100 mm (S,S) Whelk-O1. CO₂ co-solvent: isopropanol with25-50% methanol and 0.1-1% isopropylamine. Isocratic method: 20-50%co-solvent at 4 mL/min. System Pressure: 70-150 bar. Column Temperature:25 OC.

Analytical Separation Method AS(IV):

Column: 4.6×100 mm (S,S) Whelk-O1. CO₂ co-solvent: isopropanol with0.1-1% isopropylamine. Isocratic method: 20-50% co-solvent at 4 mL/min.System Pressure: 70-150 bar. Column Temperature: 25 OC.

Analytical Separation Method AS(V):

Column: 4.6×100 mm LUX Cellulose 2 from Phenomenex, Torrance, Calif. CO₂co-solvent: methanol with 0.1-1% isopropylamine. Isocratic method:20-50% co-solvent at 4 mL/min. System pressure: 70-150 bar. Columntemperature: 25° C.

Analytical Separation Method AS(VI):

Column: 4.6×100 mm LUX Cellulose 2 from Phenomenex, Torrance, Calif. CO₂co-solvent: acetonitrile with 10-25% methanol and 0.1-1% isopropylamine.Isocratic method: 50-65% co-solvent at 4 mL/min. System pressure:100-125 bar. Column temperature: 25° C.

Analytical Separation Method AS(VII):

Column: 4.6×100 mm 2-Ethylpyridine from Princeton Chromatography,Cranbury, N.J. CO₂ co-solvent: isopropanol with 0.1% isopropylamine.Isocratic method: 15% co-solvent at 4 mL/min. System pressure 100 bar.Column temperature: 25° C.

Analytical Separation Method AS(VIII):

Column: 4.6×100 mm Pyridyl Amide from ES Industries, West Berlin, N.J.CO₂ co-solvent: isopropanol with 10-90% methanol and 0.1-1%isopropylamine. Isocratic method: 5% co-solvent at 4 mL/min. Systempressure: 100 bar. Column temperature: 25° C.

Analytical Separation Method AS(IX):

Column: 4.6×100 mm cm RegisPack®. CO₂ co-solvent: ethanol with 1%isopropylamine. Isocratic method: 25% co-solvent at 80 mL/min. Systempressure: 100 bar. Column temperature: 25° C.

Structure/Compound # Separation method & data

Separated by preparative separation method PS(I) and analyzed byanalytical separation method AS(I). Faster moving enantiomer (fraction1, Example 1.1a): Rt = 2.0 min, 100% ee. Slower moving enantiomer(fraction 2, Example (1.1b): Rt = 3.1 min, 99.0% ee. mGluR5 PAM EC₅₀:++.

Separated by preparative separation method PS(II) and analyzed byanalytical separation method AS(II). Faster moving enantiomer (fraction1, Example 1.2a): Rt = 2.0 min, 100% ee. mGluR5 PAM EC₅₀: ++++. Slowermoving enantiomer (fraction 2, Example 1.2b): Rt = 3.1 min, 99.0% ee.mGluR5 PAM EC₅₀: +.

Separated by preparative separation method PS(III) and analyzed byanalytical separation method AS(III). Faster moving enantiomer (fraction1, Example 1.3a): Rt = 2.5 min, 97.6% ee. mGluR5 PAM EC₅₀: +++++. Slowermoving enantiomer (fraction 2, Example 1.3b): Rt = 3.6 min, 95.4% ee.mGluR5 PAM EC₅₀: ++.

Separated by preparative separation method PS(IV) and analyzed byanalytical separation method AS(IV). Faster moving enantiomer (fraction1, Example 1.8a): Rt = 2.0 min, 99.2% ee. mGluR5 PAM EC₅₀: ++++. Foldshift at 1 μM: +++. Slower moving enantiomer (fraction 2, Example 1.8b):Rt = 2.9 min, 99.5% ee. mGluR5 PAM EC₅₀: +++. Fold shift at 1 μM: +.

Separated by preparative separation method PS(II) and analyzed byanalytical separation method AS(II). Faster moving enantiomer (fraction1, Example 1.9a): Rt = 2.4 min, 100% ee. mGluR5 PAM EC₅₀: +++. Slowermoving enantiomer (fraction 2, Example 1.9b): Rt = 3.2 min, 98.8% ee.mGluR5 PAM EC₅₀: +.

Separated by preparative separation method PS(I) and analyzed byanalytical separation method AS(I). Faster moving enantiomer (fraction1, Example 1.11a): Rt = 1.1 min, 98.1% ee. mGluR5 PAM EC₅₀: +++++.Slower moving enantiomer (fraction 2, Example 1.11b): Rt = 1.6 min, 100%ee. mGluR5 PAM EC₅₀: ++++.

Separated by preparative separation method PS(II) and analyzed byanalytical separation method AS(II). Faster moving enantiomer (fraction1, Example 1.13a): Rt = 2.4 min, 100% ee. mGluR5 PAM EC₅₀: +++. Slowermoving enantiomer (fraction 2, Example 1.13b): Rt = 3.0 min, 100% ee.

Separated by preparative separation method PS(I) and analyzed byanalytical separation method AS(I). Faster moving enantiomer (fraction1, Example 2.1a): Rt = 2.5 min, 98.2% ee. mGluR5 PAM EC₅₀: ++++. Slowermoving enantiomer (fraction 2, Example 2.1b): Rt = 3.4 min, 96.4% ee.mGluR5 PAM EC₅₀: Fold shift at 1 μM: ++.

Separated by preparative separation method PS(I) and analyzed byanalytical separation method AS(I). Faster moving enantiomer (fraction1, Example 2.2a): Rt = 2.0 min, 97.8% ee. Slower moving enantiomer(fraction 2, Example 2.2b): Rt = 2.6 min, 97.3% ee. mGluR5 PAM EC₅₀:++++.

Separated by preparative separation method PS(I) and analyzed byanalytical separation method AS(I). Faster moving enantiomer (fraction1, Example 2.3a): Rt = 1.8 min, 98.8% ee. Slower moving enantiomer(fraction 2, Example 2.3b): Rt = 1.9 min, 99.0% ee. mGluR5 PAM EC₅₀:+++++.

Separated by preparative separation method PS(II) and analyzed byanalytical separation method AS(II). Faster moving enantiomer (fraction1, Example 2.4a): Rt = 4.4 min, 100% ee. Slower moving enantiomer(fraction 2, Example 2.4b): Rt = 4.8 min, 100% ee. mGluR5 PAM EC₅₀:+++++.

Separated by preparative separation method PS(I) and analyzed byanalytical separation method AS(I). Faster moving enantiomer (fraction1, Example 2.5a): Rt = 1.6 min, 100% ee. mGluR5 PAM EC₅₀: +++. Foldshift at 10 μM: +++. Slower moving enantiomer (fraction 2, Example2.5b): Rt = 2.0 min, 98.1% ee. mGluR5 PAM EC₅₀: +++. Fold shift at 10μM: +++.

Separated by preparative separation method PS(II) and analyzed byanalytical separation method AS(II). Faster moving enantiomer (fraction1, Example 2.6a): Rt = 2.0 min, 100% ee. Slower moving enantiomer(fraction 2, Example 2.6b): Rt = 2.9 min, 100% ee.

Separated by preparative separation method PS(I) and analyzed byanalytical separation method AS(I). Faster moving enantiomer (fraction1, Example 2.7a): Rt = 1.2 min, 100% ee. mGluR5 PAM EC₅₀: +++. Slowermoving enantiomer (fraction 2, Example 2.7b): Rt = 2.4 min, 97.2% ee.mGluR5 PAM EC₅₀: +++++.

Separated by preparative separation method PS(I) and analyzed byanalytical separation method AS(I). Faster moving enantiomer (fraction1, Example 2.8a): Rt = 1.3 min, 100% ee. mGluR5 PAM EC₅₀: ++. Fold shiftat 10 μM: ++. Slower moving enantiomer (fraction 2, Example 2.8b): Rt =3.2 min, 99.6% ee. mGluR5 PAM EC₅₀: +++. Fold shift at 1 μM: +++.

Separated by preparative separation method PS(I) and analyzed byanalytical separation method AS(I). Faster moving enantiomer (fraction1, Example 2.9a): Rt = 1.7 min, 100% ee. mGluR5 PAM EC₅₀: ++++. Foldshift at 1 μM: +. Slower moving enantiomer (fraction 2, Example 2.9b):Rt = 2.4 min, 98.0% ee. mGluR5 PAM EC₅₀: ++++. Fold shift at 1 μM: ++.

Separated by preparative separation method PS(I) and analyzed byanalytical separation method AS(I). Faster moving enantiomer (fraction1, Example 2.10a): Rt = 3.2 min, 100% ee. mGluR5 PAM EC₅₀: +++. mGluR5Fold shift at 1 μM: ++. Slower moving enantiomer (fraction 2, Example2.10b): Rt = 5.1 min, 100% ee.

Separated by preparative separation method PS(I) and analyzed byanalytical separation method AS(I). Faster moving enantiomer (fraction1, Example 2.11a): Rt = 2.7 min, 98.8% ee. Slower moving enantiomer(fraction 2, Example 2.11b): Rt = 3.7 min, 96.0% ee.

Separated by preparative separation method PS(I) and analyzed byanalytical separation method AS(I). Faster moving enantiomer (fraction1, Example 2.12a): Rt = 1.2 min, 100% ee. mGluR5 PAM EC₅₀: +++++. Foldshift at 10 μM: +++. Slower moving enantiomer (fraction 2, Example2.12b): Rt = 2.1 min, 100% ee. mGluR5 PAM EC₅₀: +++++. Fold shift at 10μM: +.

Separated by preparative separation method PS(I) and analyzed byanalytical separation method AS(I). Faster moving enantiomer (fraction1, Example 2.13a): Rt = 2.2 min, 100% ee. mGluR5 PAM EC₅₀: ++++. Foldshift at 10 μM: +++. Slower moving enantiomer (fraction 2, Example2.13b): Rt = 3.1 min, 98.4% ee. mGluR5 PAM EC₅₀: ++++. Fold shift at 10μM: +++.

Separated by preparative separation method PS(II) and analyzed byanalytical separation method AS(II). Faster moving enantiomer (fraction1, Example 2.14a): Rt = 1.7 min, 100% ee. mGluR5 PAM EC₅₀: ++++. Slowermoving enantiomer (fraction 2, Example 2.14b): Rt = 3.4 min, 98.0% ee.mGluR5 PAM EC₅₀: +++++.

Separated by preparative separation method PS(V) and analyzed byanalytical separation method AS(V). Faster moving enantiomer (fraction1, Example 2.15a): Rt = 2.2 min, 98.0% ee. mGluR5 PAM EC₅₀: +++. Slowermoving enantiomer (fraction 2, Example 2.15b): Rt = 2.9 min, 99.4% ee.mGluR5 PAM EC₅₀: +++.

The regioisomers 1 (racemate) and 2 (racemate) were first separated byachiral preparative separation method PS(VII) and analyzed by achiralanalytical separation method AS(VII). The regiochemistry was assignedarbitrarily. Then separation of enantiomers Example 2.16a and 2.16b fromregioisomer 1 was carried by preparative separation method PS(VI) andanalyzed by analytical separation method AS(VI). Faster movingenantiomer (fraction 1, Example 2.16a): Rt = 4.8 min, 100% ee. Slowermoving enantiomer (fraction 2, Example 2.16b): Rt = 6.1 min, 95.0% ee.mGluR5 PAM EC₅₀: ++.

The separation of enantiomers Example 2.17a and 2.17b from regioisomer 2was carried by preparative separation method PS(I) and analyzed byanalytical separation method AS(I). Faster moving enantiomer (fraction1, Example 2.17a): Rt = 3.2 min, 100% ee. Slower moving enantiomer(fraction 2, Example 2.17b): Rt = 3.4 min, 98.4% ee. mGluR5 PAM EC₅₀: +.

The regioisomers 1 (racemate) and 2 (racemate) were first separated byachiral preparative separation method PS(VII) and analyzed by achiralanalytical separation method AS(VII) to give fraction 1 (arbitrarilyassigned as regioisomer 1) and fraction 2 arbitrarily assigned asregioisomer 2).

The enantiomers from fraction 1 (regioisomer 1, regiochemistry isarbitrarily assigned) were separated by preparative separation methodPS(II) and analyzed by analytical separation method AS(II). Fastermoving enantiomer (fraction 1, Example 2.22c): Rt = 1.2 min, 97.0% ee. .mGluR5 PAM EC₅₀: ++++. Slower moving enantiomer (fraction 2, Example2.22b): Rt = 1.8 min, 100% ee. mGluR5 PAM EC₅₀: ++.

Separated by preparative separation method PS(I) and analyzed byanalytical separation method AS(I). Faster moving enantiomer (fraction1, Example 3.1a): Rt = 8.8 min, 100% ee. mGluR5 PAM EC₅₀: +++. Slowermoving enantiomer (fraction 2, Example 3.1b): Rt = 10.4 min, 100% ee.mGluR5 PAM EC₅₀: ++++.

Separated by preparative separation method PS(II) and analyzed byanalytical separation method AS(II). Faster moving enantiomer (fraction1, Example 3.2a): Rt = 1.2 min, 100% ee. mGluR5 PAM EC₅₀: +. Slowermoving enantiomer (fraction 2, Example 3.2b): Rt = 1.9 min, 98.6% ee.mGluR5 PAM EC₅₀: +++.

Separated by preparative separation method PS(I) and analyzed byanalytical separation method AS(I). Faster moving enantiomer (fraction1, Example 3.3a): Rt = 2.1 min, 100% ee. mGluR5 PAM EC₅₀: +++. Foldshift at 10 μM: +++. Slower moving enantiomer (fraction 2, Example3.3b): Rt = 2.8 min, 95.0% ee. mGluR5 PAM EC₅₀: ++. Fold shift at 10 μM:+++.

Separated by preparative separation method PS(I) and analyzed byanalytical separation method AS(I). Faster moving enantiomer (fraction1, Example 3.4a): Rt = 2.1 min, 96.5% ee. mGluR5 PAM EC₅₀: +++. Foldshift at 10 μM: +++. Slower moving enantiomer (fraction 2, Example3.4b): Rt = 2.8 min, 98.8% ee. mGluR5 PAM EC₅₀: +++. Fold shift at 10μM: ++.

Separated by preparative separation method PS(II) and analyzed byanalytical separation method AS(II). Faster moving enantiomer (fraction1, Example 3.9a): Rt = 2.8 min, 100% ee. mGluR5 PAM EC₅₀: +++. Slowermoving enantiomer (fraction 2, Example 3.9b): Rt = 3.9 min, 100% ee.mGluR5 PAM EC₅₀: +++.

Separated by preparative separation method PS(II) and analyzed byanalytical separation method AS(II). Faster moving enantiomer (fraction1, Example 3.10a): Rt = 0.8 min, 97.6% ee. mGluR5 PAM EC₅₀: ++. Slowermoving enantiomer (fraction 2, Example 3.10b): Rt = 2.1 min; 99.2% ee.mGluR5 PAM EC₅₀: +++. Fold shift at 1 μM: +++.

Separated by preparative separation method PS(II) and analyzed byanalytical separation method AS(II). Faster moving enantiomer (fraction1, Example 3.11a): Rt = 0.9 min, 100% ee. Slower moving enantiomer(fraction 2, Example 3.11b): Rt = 2.3 min; 99.8% ee. mGluR5 PAM EC₅₀:++++. Fold shift at 1 μM: ++.

Separated by preparative separation method PS(II) and analyzed byanalytical separation method AS(II). Faster moving enantiomer (fraction1, Example 3.12a): Rt = 1.5 min, 100% ee. mGluR5 PAM EC₅₀: +++++. Slowermoving enantiomer (fraction 2, Example 3.12b): Rt = 2.2 min, 99.5% ee.mGluR5 PAM EC₅₀: ++++.

Separated by preparative separation method PS(I) and analyzed byanalytical separation method PS(I). Faster moving enantiomer (fraction1, Example 3.13a): Rt = 1.8 min, 98.6% ee. mGluR5 PAM EC₅₀: +++++. Foldshift at 1 μM: +++. Slower moving enantiomer (fraction 2, Example3.13b): Rt = 2.6 min, 98.8% ee. mGluR5 PAM EC₅₀: ++++. Fold shift at 1μM: +++.

Separated by preparative separation method PS(II) and analyzed byanalytical separation method AS(II). Faster moving enantiomer (fraction1, Example 3.14a): Rt = 1 min, 100% ee. mGluR5 PAM EC₅₀: +++. Fold shiftat 1 μM: +++. Slower moving enantiomer (fraction 2, Example 3.14b): Rt =3.3 min, 99.6% ee. mGluR5 PAM EC₅₀: +++. Fold shift at 1 μM: +++.

Separated by preparative separation method PS(II) and analyzed byanalytical separation method AS(II). Faster moving enantiomer (fraction1, Example 3.20a): Rt = 1 min, 100% ee. mGluR5 PAM EC₅₀: +++++. Foldshift at 10 μM: +++. Slower moving enantiomer (fraction 2, Example3.20b): Rt = 3.3 min, 99.6% ee.

Separated by preparative separation method PS(I) and analyzed byanalytical separation method AS(I). Faster moving enantiomer (fraction1, Example 3.24a): Rt = 1.4 min, 99.1% ee. mGluR5 PAM EC_(50:) +++++.Fold shift at 1 μM: +++. Slower moving enantiomer (fraction 2, Example3.24b): Rt = 2.0 min, 99.2% ee. mGluR5 PAM EC₅₀: +++++. Fold shift at 1μM: +++.

The regioisomers and enantiomers were separated by two chiralchromatographies. The regiochemistry was assigned arbitrarily.Enantiomers 3.30a and 3.30b were separated from regioisomers 1 bypreparative separation method PS(I) and analyzed by analyticalseparation method AS(I). Faster moving enantiomer (fraction 1, Example3.30c): Rt = 3.3 min, 100% ee. mGluR5 PAM EC₅₀: ++++. Fold shift at 10μM: +++. Slower moving enantiomer (fraction 2, Example 3.30d): Rt = 4.1min, 98.4% ee. mGluR5 PAM EC₅₀: ++++. Fold shift at 10 μM: +.

Enantiomers 3.30c and 3.30d were separated from regioisomer 2 bypreparative separation method PS(II) and analyzed by analyticalseparation method AS(II). The regiochemistry was assigned arbitrarily.Faster moving enantiomer (fraction 1, Example 3.30e): Rt = 1.2 min, 100%ee. Slower moving enantiomer (fraction 2, Example 3.30f): Rt = 2.0 min,98.4% ee. mGluR5 PAM EC₅₀: ++++. Fold shift at 10 μM: ++.

The two regioisomers were separated by chromatography on achiral columnby preparative separation method PS(VIII) and analytical separationmethod AS(VIII) to give regioisomer 1 and regioisomer 2 (Theregiochemistry was assigned arbitrarily). The separation of enantiomersfrom regioisomer 1 (Example 3.31a) was carried by preparative separationmethod PS(IX) and analyzed by analytical separation method AS(IX) toprovide Example 3.31c and 3.31d (The absolute stereochemistry wasarbitrarily assigned). Faster moving enantiomer (fraction 1, Example3.31c): Rt = 2.8 min, 96.6% ee. mGluR5 PAM EC₅₀: +++. Slower movingenantiomer (fraction 2, Example 3.31d): Rt = 3.2 min, 99.6% ee. mGluR5PAM EC₅₀: +++. Fold shift at 1 μM: +++.

The separation of enantiomers from regioisomer 2 (example 3.31b wascarried out by preparative separation method PS(II) and analyzed byanalytical separation method AS(II) to give Example 3.31e, and 3.31f(The absolute stereochemistry was arbitrarily assigned). Faster movingenantiomer (fraction 1, Example 3.31e): Rt = 1.4 min, 100% ee. mGluR5PAM EC₅₀: +++. Fold shift at 1 μM: +++. Slower moving enantiomer(fraction 2, Example 3.31f): Rt = 3.1 min, 100% ee. mGluR5 PAM EC₅₀:+++.

Preparative separation method PS(II) generated two fractions (Fractions1 and 2). Fraction 1 contained three peaks, while fraction 2 was asingle peak. Fraction 1 was then put through preparative separationmethod PS(VI) where the three peaks were resolved (Fractions 3, 4 and5). The collected fractions were analyzed by analytical separationmethods AS(II) and AS(VI). Fraction 1, Example 3.32c: Rt from analyticalseparation methods AS(II) and AS(VI): 3.4 min and 3.1 min, respectively,95.6% ee. Fraction 2, Example3.2d: Rt from analytical separation methodsAS(II) and AS(VI): 1.8 min and 3.1 min, respectively, 100% ee. mGluR5PAM EC₅₀: +++.

Fraction 3, Example 3.2e: Rt from analytical separation methods AS(II)and AS(VI): 1.8 min and 3.7 min, respectively, 100% ee. mGluR5 PAM EC₅₀:+++. Fraction 4, Example 3.2f: Rt from analytical separation methodsAS(II) and AS(VI): 1.8 min and 4.1 min, respectively, 97.8% ee. mGluR5PAM EC₅₀: +++++.

Prophetic Compounds

Compound Synthesis Method & Data

May be synthesized from tert-butyl 3- oxopyrrolidine-1-carboxylate,2-amino-4- bromobenzoic acid, and 2-ethynylpyridine according to GeneralExperimentals G22, G24, C4, F3, B1, and A1. Example 1.212,2-difluoro-6′-(pyridin-2-ylethynyl)-1′H-spiro[cyclopropane-1,2′-pyrrolo[2,1-b]quinazolin]-9′(3′H)-one

May be synthesized from isobutyronitrile, 2-amino-4-bromobenzoic acid,ethynyltrimethylsilane, and 2-bromo-4- methyloxazole according toGeneral Experimentals C6, B1, and A2. Example 2.488,8-dimethyl-3-((4-methyloxazol-2-yl)ethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

May be synthesized from isobutyronitrile, 2-amino-4-bromobenzoic acid,ethynyltrimethylsilane, and 2-bromo-5- methyl-1,3,4-oxadiazole accordingto General Experimentals C6, B1, and A2. Example 2.528,8-dimethyl-3-((5-methyl-1,3,4-oxadiazol-2-yl)ethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

May be synthesized from isobutyronitrile, 2-amino-4-bromobenzoic acid,ethynyltrimethylsilane, and 2-bromo-4- fluoropyrimidine according toGeneral Experimentals C6, B1, and A2. Example 2.533-((4-fluoropyrimidin-2-yl)ethynyl)-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

May be synthesized from isobutyronitrile, 2-amino-4-bromobenzoic acid,ethynyltrimethylsilane, and 2-bromo-5,6-dihydro-4H-cyclopenta[d]thiazole according to General Experimentals C6,B1, and A2. Example 2.563-((5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl)ethynyl)-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

May he synthesized from isobutyronitrile, 2-amino-4-bromobenzoic acid,ethynyltrimethylsilane, and 2-bromo- 4,5,6,7-tetrahydrobenzo[d]thiazoleaccording to General Experimentals C6, B1, and A2. Example 2.578,8-dimethyl-3-((4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)ethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

May be synthesized from tert-butyl 1-oxa-6-azaspiro[3.5]nonane-6-carboxylate, 2- amino-4-bromobenzoic acid, and2- ethynylpyridine according to General Experimentals C4, F3, B1, andA1. Example 2.593′-(pyridin-2-ylethynyl)-6′,7′-dihydrospiro[oxetane-2,8′-pyrido[2,1-b]quinazolin]-11′(9′H)-one

May be synthesized from cyclopropanecarbonitrile, ethyl acrylate,2-amino-4-bromobenzoic acid, and 2- ethynylpyridine according to GeneralExperimentals C6, B1, and A1 or from tert-butyl 5-azaspiro[2.5]octane-5-carboxylate, 2-amino-4-bromobenzoic acid, and 2-ethynylpyridineaccording to General Experimentals C4, F3, B1, and A1. Example 2.603′-(pyridin-2-ylethynyl)-6′,7′-dihydrospiro[cyclopropane-1,8′-pyrido[2,1-b]quinazolin]-11′(9′H)-one

May be synthesized from tert-butyl 1-methyl-1,7-diazaspiro[4.5]decane-7- carboxylate, 2-amino-4-bromobenzoicacid, and 2-ethynylpyridine according to General Experimentals C4, F3,B1, and A1. Example 2.61 1′-methyl-3-(pyridin-2-ylethynyl)-6,7-dihydrospiro[pyrido[2,1-b]quinazoline-8,2′-pyrrolidin]- 11(9H)-one

May he synthesized from 1-((9H-fluoren- 9-yl)methyl) 7-tert-butyl 1,7-diazaspiro[4.5]decane-1,7-dicarboxylate, 2-amino-4-bromobenzoic acid,and 2- ethynylpyridine according to General Experimentals C4, F3, F4,B1, and A1. Example 2.62 3-(pyridin-2-ylethynyl)-6,7-dihydrospiro[pyrido[2,1-b]quinazoline-8,2′-pyrrolidin]- 11(9H)-one

May be synthesized from 3,3,3-trifluoro- 2-methylpropanenitrile(prepared from methylation of 3,3,3- trifluoropropanenitrile bydeprotonation with LDA and methylation with MeI), ethyl acrylate,2-amino-4-bromobenzoic acid, and 2-ethynylpyridine according to GeneralExperimentals C6, B1, and A1. Example 2.638-methyl-3-(pyridin-2-ylethynyl)-8-(trifluoromethyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

May be synthesized from dimethyl malonate, (Z)-1,4-dichlorobut-2-ene, 2-amino-4-bromobenzoic acid, and 2- ethynylpyridine according to GeneralExperimentals H4, B1, and A1. Example 2.648,8-bis(fluoromethyl)-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

May be synthesized from 5- hydroxypiperidin-2-one, 2-amino-4-bromobenzoic acid, and 2-ethynylpyridine according to GeneralExperimentals F1, B1, F4, G16, G8, E1 and A1. Example 2.658-cyclopropyl-8-fluoro-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

May be synthesized from 5- hydroxypiperidin-2-one, 2-amino-4-bromobenzoic acid, and 2-ethynylpyridine according to GeneralExperimentals F1, B1, F4, G16, G8, G25 and A1. Example 2.663-(pyridin-2-ylethynyl)-8-vinyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

May be synthesized from tert-butyl 5,6-dihydropyridine-1(2H)-carboxylate, 2- amino-4-bromobenzoic acid, and 2-ethynylpyridine according to General Experimentals G24, C4, B1, and A1.Example 2.67 1,1-difluoro-5-(pyridin-2-ylethynyl)-1a,2,10,10a-tetrahydrocyclopropa[4,5]pyrido[2,1-b]quinazolin-8(1H)-one

May be synthesized from isobutyronitrile, 2-amino-4-bromobenzoic acid,and 3- ethynylpyridine according to General Experimentals C6, B1, and A1or from isobutyronitrile, 2-amino-4-bromobenzoic acid,ethynyltrimethylsilane, and 3- chloropyridine or 3-bromopyridineaccording to General Experimentals C6, B1, and A2. Example 2.718,8-dimethyl-3-(pyridin-3-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

May be synthesized from isobutyronitrile, 2-amino-4-bromobenzoic acid,and 4- ethynylpyridine according to General Experimentals C6, B1, and A1or from isobutyronitrile, 2-amino-4-bromobenzoic acid,ethynyltrimethylsilane, and 4- chloropyridine or 4-bromopyridineaccording to General Experimentals C6, B1, and A2. Example 2.728,8-dimethyl-3-(pyridin-4-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

May be synthesized from isobutyronitrile, 2-amino-4-bromobenzoic acid,and 1- ethynyl-3-fluorobenzene according to General Experimentals C6,B1, and A1 or from isobutyronitrile, 2-amino-4- bromobenzoic acid,ethynyltrimethylsilane, and 1-bromo-3-fluorobenzene or 1-chloro-3-fluorobenzene according to General Experimentals C6, B1, and A2.Example 2.74 3-((3-fluorophenyl)ethynyl)-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

May be synthesized from isobutyronitrile, 2-amino-4-bromobenzoic acid,and 1- ethynyl-2,3-difluorobenzene according to General ExperimentalsC6, B1, and A1 or from isobutyronitrile, 2-amino-4- bromobenzoic acid,ethynyltrimethylsilane, and 1-bromo-2,3-difluorobenzene or 1-chloro-2,3-difluorobenzene according to General Experimentals C6, B1,and A2. Example 2.763-((2,3-difluorophenyl)ethynyl)-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

May be synthesized from isobutyronitrile, 2-amino-4-bromobenzoic acid,and 1- ethynyl-2,4-difluorobenzene according to General ExperimentalsC6, B1, and A1 or from isobutyronitrile, 2-amino-4- bromobenzoic acid,ethynyltrimethylsilane, and 1-bromo-2,4-difluorobenzene or 1-chloro-2,4-difluorobenzene according to General Experimentals C6, B1,and A2. Example 2.773-((2,4-difluorophenyl)ethynyl)-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

May be synthesized from isobutyronitrile, 2-amino-4-bromobenzoic acid,and 2- ethynyl-1,4-difluorobenzene according to General ExperimentalsC6, B1, and A1 or from isobutyronitrile, 2-amino-4- bromobenzoic acid,ethynyltrimethylsilane, and 2-bromo-1,4-difluorobenzene or 2-chloro-1,4-difluorobenzene according to General Experimentals C6, B1,and A2. Example 2.783-((2,5-difluorophenyl)ethynyl)-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

May be synthesized from isobutyronitrile, 2-amino-4-bromobenzoic acid,and 4- ethynyl-1,2-difluorobenzene according to General ExperimentalsC6, B1, and A1 or from isobutyronitrile, 2-amino-4- bromobenzoic acid,ethynyltrimethylsilane, and 4-bromo-1,2-difluorobenzene or 4-chloro-1,2-difluorobenzene according to General Experimentals C6, B1,and A2. Example 2.793-((3,4-difluorophenyl)ethynyl)-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

May be synthesized from isobutyronitrile, 2-amino-4-bromobenzoic acid,and 2- ethynyl-1,3-difluorobenzene according to General ExperimentalsC6, B1, and A1 or from isobutyronitrile, 2-amino-4- bromobenzoic acid,ethynyltrimethylsilane, and 2-chloro-1,3-difluorobenzene or 2-bromo-1,3-difluorobenzene according to General Experimentals C6, B1, andA2. Example 2.803-((2,6-difluorophenyl)ethynyl)-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

May be synthesized from isobutyronitrile, 2-amino-4-bromobenzoic acid,and 1- ethynyl-3,5-difluorobenzene according to General ExperimentalsC6, B1, and A1 or from isobutyronitrile, 2-amino-4- bromobenzoic acid,ethynyltrimethylsilane, and 1-bromo-3,5-difluorobenzene or 1-chloro-3,5-difluorobenzene according to General Experimentals C6, B1,and A2. Example 2.813-((3,5-difluorophenyl)ethynyl)-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

May be synthesized from isobutyronitrile, 2-amino-4-bromobenzoic acid,and 4- ethynyl-2,5-difluoropyridine according to General ExperimentalsC6, B1, and A1 or from isobutyronitrile, 2-amino-4- bromobenzoic acid,ethynyltrimethylsilane, and 4-bromo-2,5-difluoropyridine or 4-chloro-2,5-difluoropyridine according to General Experimentals C6, B1,and A2. Example 2.823-((2,5-difluoropyridin-4-yl)ethynyl)-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

May be synthesized from isobutyronitrile, 2-amino-4-bromobenzoic acid,and 2- ethynyl-6-fluoropyridine according to General Experimentals C6,B1, and A1 or from isobutyronitrile, 2-amino-4- bromobenzoic acid,ethynyltrimethylsilane, and 2-chloro-6-fluoropyridine or 2-bromo-6-fluoropyridine according to General Experimentals C6, B1, and A2.Example 2.833-((6-fluoropyridin-2-yl)ethynyl)-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

May be synthesized from isobutyronitrile, 2-amino-4-bromobenzoic acid,and 2- ethynyl-5-fluoropyridine according to General Experimentals C6,B1, and A1 or from isobutyronitrile, 2-amino-4- bromobenzoic acid,ethynyltrimethylsilane, and 2-chloro-5-fluoropyridine or 2-bromo-5-fluoropyridine according to General Experimentals C6, B1, and A2.Example 2.843-((5-fluoropyridin-2-yl)ethynyl)-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

May be synthesized from isobutyronitrile, 2-amino-4-bromobenzoic acid,and 2- ethynyl-4-fluoropyridine according to General Experimentals C6,B1, and A1 or from isobutyronitrile, 2-amino-4- bromobenzoic acid,ethynyltrimethylsilane, and 2-chloro-4-fluoropyridine or 2-bromo-4-fluoropyridine according to General Experimentals C6, B1, and A2.Example 2.85 3-((4-fluoropyridin-2-yl)ethynyl)-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

May be synthesized from isobutyronitrile, 2-amino-4-bromobenzoic acid,and 3- ethynyl-2,4-difluoropyridine according to General ExperimentalsC6, B1, and A1 or from isobutyronitrile, 2-amino-4- bromobenzoic acid,ethynyltrimethylsilane, and 3-chloro-2,4-difluoropyridine or 3-bromo-2,4-difluoropyridine according to General Experimentals C6, B1,and A2. Example 2.933-((2,4-difluoropyridin-3-yl)ethynyl)-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

May be synthesized from isobutyronitrile, 2-amino-4-bromobenzoic acid,and 4- ethynyl-2,3-difluoropyridine according to General ExperimentalsC6, B1, and A1 or from isobutyronitrile, 2-amino-4- bromobenzoic acid,ethynyltrimethylsilane, and 4-chloro-2,3-difluoropyridine or 4-bromo-2,3-difluoropyridine according to General Experimentals C6, B1,and A2. Example 2.943-((2,3-difluoropyridin-4-yl)ethynyl)-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

May be synthesized from tert-butyl 1,4-diazabicyclo[3.2.1]octane-4-carboxylate, 2-amino-4-bromobenzoic acid,and 2- ethynylpyridine according to General Experimentals C4, F3, B1,and A1. Example 3.39 10-(pyridin-2-ylethynyl)-4,5-dihydro-1H-2,5-methano[1,4]diazepino[2,1-b]quinazolin-7(3H)-one

May be synthesized from tert-butyl 3- oxoazepane-1-carboxylate,2-amino-4- bromobenzoic acid, and 2-ethynylpyridine according to GeneralExperimentals E4, G22, G23, C4, F3, B1, and A1. Example 3.418-fluoro-3-(pyridin-2-ylethynyl)-7,8-dihydro-6H-spiro[azepino[2,1-b]quinazoline-9,1′-cyclopropan]-12(10H)-one

May be synthesized from isobutyronitrile, 2-amino-4-nitrobenzoic acid,and picolinic acid according to General Experimentals C6, B5, G29 andG28. Example 4.13 N-(8,8-dimethyl-11-oxo-7,8,9,11-tetrahydro-6H-pyrido[2,1-b]quinazolin-3-yl)picolinamide

It will be understood that the invention has been described by way ofexample only and modifications may be made whilst remaining within thescope and the spirit of the invention.

The invention claimed is:
 1. A compound, wherein said compound is:

or a pharmaceutically acceptable salt thereof.
 2. The compound accordingto claim 1, wherein said compound is:

or a pharmaceutically acceptable salt thereof.
 3. The compound accordingto claim 1, wherein said compound is:

or a pharmaceutically acceptable salt thereof.
 4. A method of treatingFragile X, comprising the step of administering the compound:

or a pharmaceutically acceptable salt thereof, to a patient or subjectin need thereof.
 5. The method according to claim 4, wherein saidcompound is:

or a pharmaceutically acceptable salt thereof.
 6. The method accordingto claim 4, wherein said compound is:

or a pharmaceutically acceptable salt thereof.